https://proteopedia.org/api.php?action=feedcontributions&feedformat=atom&user=Chandler+MitchellProteopedia - User contributions [en]2026-09-16T07:51:05ZUser contributionsMediaWiki 1.43.8https://proteopedia.org/index.php?title=Sandbox_Reserved_1172&diff=2587675Sandbox Reserved 11722016-04-18T23:57:09Z<p>Chandler Mitchell: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Central_Metabolism}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Lysophosphatidic Acid Receptor 1==<br />
<StructureSection load='4z34' size='340' side='right' caption='Cartoon representation of the LPA1 protein and its antagonist, ON7, colored in white. ([https://en.wikipedia.org/wiki/Protein_Data_Bank PDB] code [http://www.rcsb.org/pdb/explore/explore.do?structureId=4z34 4Z34]) ' scene='72/721543/Overallrainbow2/1'><br />
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<br />
== Introduction ==<br />
Lysophosphatidic Acid Receptor 1 (commonly referred to as LPA<sub>1</sub>) is a [[G protein-coupled receptor]] and one of 6 different LPA receptors (LPA<sub>1</sub>-LPA<sub>6</sub>). These receptors bind the phospholipid derivative [https://en.wikipedia.org/wiki/Lysophosphatidic_acid lysophosphatidic acid (LPA)], a signaling molecule that acts as a potent [https://en.wikipedia.org/wiki/Mitogen mitogen] upon binding to one of its six receptors.<ref name="regpeps">PMID: 26091040</ref> LPA<sub>1</sub> is part of the larger [http://jb.oxfordjournals.org/content/131/6/767 EDG receptor family], which includes the more widely studied sphingosine 1-phopshate receptors.<ref name="regpeps">PMID: 26091040</ref> This receptor is responsible for initiating several different signaling cascades with different molecules and G-proteins.<ref name = 'Yung'>Yung, Y. C., N. C. Stoddard, and J. Chun. "LPA Receptor Signaling: Pharmacology, Physiology, and Pathophysiology." The Journal of Lipid Research 55.7 (2014): 1192-214. Web. 17 Feb. 2016.' </ref> These cascades ultimately result in growth, survival, and movement of cells, as well as neural cell development.<ref name = 'Chun'>Chun, J., Hla, T., Spiegel, S., and Moolenaar, W.H. “Lysophospholipid Receptors: Signaling and Biochemistry.” John Wiley & Sons, Inc. (2013) pp.i-xviii. 5 Feb. 2016.' </ref><br />
== Structure ==<br />
[[Image:Pic2proteo3.png|275 px|left|thumb|Figure 1: Surface representation of the LPA<sub>1</sub> receptor in tan interacting with its antagonist, ON7, shown in green and red sticks.The exterior of the protein was partially cut away to display the interior binding pocket.]]<br />
The LPA<sub>1</sub> receptor protein is composed of 364 amino acids with a molecular weight of approximately 41 kDa. Common to all G-protein coupled receptors, LPA<sub>1</sub> contains seven [http://kinemage.biochem.duke.edu/teaching/anatax/html/anatax.2a.html alpha helices] which make up the seven transmembrane spanning domains with three intracellular loops and three extracellular loops.<ref name = 'Hernández-Méndez'>Hernández-Méndez, Aurelio, Rocío Alcántara-Hernández, and J. Adolfo García-Sáinz. "Lysophosphatidic Acid LPA1-3 Receptors: Signaling, Regulation and in Silico Analysis of Their Putative Phosphorylation Sites." Receptors & Clinical Investigation Receptor Clin Invest 1.3 (2014). Web. 15 Feb. 2016.' </ref> Within these helices is a binding pocket which stabilizes the binding of its ligand, LPA (Figure 1).<br />
=== Key Ligand Interactions ===<br />
[[Image:Amphbindingfinal.png|275 px|right|thumb|Figure 2: Electrostatic illustration of the amphipathic binding pocket of the LPA<sub>1</sub> receptor. This binding pocket was revealed by cutting away the exterior or the protein. This binding pocket, located in the interior of the protein, has both polar and nonpolar regions. The blue and red coloration highlight the positively and negatively charged regions, respectively, and the white color shows the nonpolar region of the binding pocket.]]<br />
The biological ligand of the LPA<sub>1</sub> receptor receptor is [https://en.wikipedia.org/wiki/Lysophosphatidic_acid lysophosphatidic acid (LPA)], a phospholipid that contains a long, nonpolar tail, a phosphate head, a chiral hydroxyl group, and an ester group. This receptor provides specificity for its ligand by the amphipathic binding pocket; the positive region on the left hand side of the pocket stabilizes the LPA's phosphate group, the nonpolar region at the bottom of the binding pocket stabilizes the hydrophobic tail of LPA, and the polar region at the top of the pocket stabilize binding of the ester and hydroxyl group (Figure 2). [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=8589 ONO-9780307 (ON7)] is an antagonist for LPA due to its large nonpolar region, chiral hydroxyl group, ester, and carboxylic acid which all resemble portions of the LPA molecule. Four separate interactions with this antagonist of LPA<sub>1</sub> help demonstrate the key interactions that stabilize the binding of the LPA phospholipid to this receptor. In the nonpolar region of the binding pocket, <scene name='72/721543/Nonpolar/2'>three non polar residues</scene> of LPA<sub>1</sub> stabilize the large nonpolar group of ON7. At the polar region, the ligand binding is stabilized by <scene name='72/721543/Arg124gln125/4'>Arg124 and Glu125</scene> forming ionic and polar interactions with the carboxylic acid and the hydroxyl group of ON7.<ref name="regpeps">PMID: 26091040</ref> In addition, interplay between <scene name='72/721543/Lys39_and_glu293/8'>Glu293 and Lys39</scene> causes another stabilizing component with the ON7 antagonist. Glu293 forms polar interactions with Lys39, positioning it in close proximity to to the carboxylic acid of ON7, which then interactions with Lys39 via ionic bonding.<ref name="regpeps">PMID: 26091040</ref> While Lys39 is highly conserved among all six LPA receptors, a neighboring histidine residue is specific to the LPA<sub>1</sub> receptor. <scene name='72/721543/His40/4'>His40</scene> forms both ionic and polar interactions with the carboxylic acid of ON7. Protonation of this residue greatly affects the binding affinity of LPA, leading to an increase in the pathways associated with cell proliferation and migration. Because cancerous tumors create acidic environments where His40 is protonated, this residue is an important link to tumor growth and cancer cell movement.<ref name="regpeps">PMID: 26091040</ref><br />
<br />
<br />
== Function ==<br />
The LPA<sub>1</sub> receptor is present in nearly all cells and tissues, and deletion of the LPA<sub>1</sub> receptor has physiological effects on every organ system, indicating its wide range of functions. Specifically, this receptor initiates downstream signaling cascades with three G<sub>α</sub> proteins: G<sub>i/o</sub>, G<sub>q/11</sub>, and G<sub>12/13</sub>. Specifically, G<sub>α</sub> proteins begin signaling cascades that activate [https://en.wikipedia.org/wiki/Phospholipase_C phospholipase C] and [[MAPK]]s that signal for cell proliferation, survival, and migration. <ref name = 'Yung'>Yung, Y. C., N. C. Stoddard, and J. Chun. "LPA Receptor Signaling: Pharmacology, Physiology, and Pathophysiology." The Journal of Lipid Research 55.7 (2014): 1192-214. Web. 17 Feb. 2016.' </ref> Despite this receptor being expressed ubiquitously, LPA<sub>1</sub> is highly expressed in neural tissue, aiding in several different neurodevelopmental processes including growth and folding of the [https://www.dartmouth.edu/~rswenson/NeuroSci/chapter_11.html cerebral cortex] and the growth, survival, and migration of neural [https://en.wikipedia.org/wiki/Progenitor_cell progenitor cells].<ref name = 'Chun'>Chun, J., Hla, T., Spiegel, S., and Moolenaar, W.H. “Lysophospholipid Receptors: Signaling and Biochemistry.” John Wiley & Sons, Inc. (2013) pp.i-xviii. 5 Feb. 2016.' </ref> Finally, LPA<sub>1</sub> receptors expressed in neural tissue act through a signaling pathway with the [https://en.wikipedia.org/wiki/RAC1 Rac1] G-protein to aid in Schwann cell migration and myelination.<ref name="number5">PMID: 24115248</ref><br />
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<br />
<br />
== Receptor Comparison ==<br />
<br />
=== Sphingosine 1-Phosphate Receptor ===<br />
LPA<sub>1</sub> belongs to the EDG (endothelial differentiation gene) family of [https://en.wikipedia.org/wiki/Lysophospholipid_receptor lysophospholipid receptors]. This family also includes the [https://en.wikipedia.org/wiki/S1PR1 sphingosine 1-phosphate receptor 1] (S1P<sub>1</sub>), which shares many structural similarities to LPA<sub>1</sub>. In fact, the transmembrane regions share a sequence identity of 41%. <ref name = 'Chun, E.'>Chun, E., Thompson, A.A., Lui, W., Roth, C.B., Griffith, M.T., Katritch, V., Kunken, J., Xu, F., Cherezov, V., Hanson, M.A., and Stevens, R.C. “Fusion partner tool chest for the stabilization and crystallization of G protein-coupled receptors.” Structure 20, (2012) 967-976.' </ref> A defining difference between these two receptors is their mode of ligand access to the binding site. The hydrophobic [https://en.wikipedia.org/wiki/Sphingosine-1-phosphate S1P ligand] enters S1P<sub>1</sub> via the membrane. LPA<sub>1</sub> differs and utilizes an extracellular opening that allows LPA access from the extracellular space (Figure 3). <ref name="regpeps">PMID: 26091040</ref> Structural evidence for this altered ligand binding pathway includes global changes in the positioning of the extracellular loops (ECL) and transmembrane helices (TM). Specifically, a slight divergence of <scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene>, which is positioned 3 Å closer to TMVII compared to S1P<sub>1</sub>, and a repositioning of <scene name='72/721543/Ecl_regions/1'>ECL3</scene>, resulting in a divergence of 8 Å from S1P<sub>1</sub> result in ligand access via the extracellular space. <ref name="regpeps">PMID: 26091040</ref> This narrowing of the gap between TMI and TMVII blocks membrane ligand access in LPA<sub>1</sub>, while the greater distance between ECL3 and the other extracellular loops promotes extracellular access for LPA<sub>1</sub>. Additionally, ECL0 is helical in S1P<sub>1</sub>, but <scene name='72/721543/Ecl02ndstructure/1'>lacks secondary structure</scene> in LPA<sub>1</sub>. This increased flexibility that results from ECL0 lack of secondary structure in LPA<sub>1</sub> further promotes favorable LPA access to the binding pocket from the extracellular space. <ref name="regpeps">PMID: 26091040</ref><br />
<br />
<br />
[[Image:ECL3DistanceCM.png|200 px|left|thumb|Figure 3: Extracellular ligand access pathway on LPA<sub>1</sub>. Compared to S1P<sub>1</sub>, ECL3 shown in red is positioned 8 Å further from ECL0 and ECL2 shown in green. This largely contributes to the altered ligand binding pathway between LPA<sub>1</sub>, and S1P<sub>1</sub>]]<br />
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=== Endocannabinoid Receptor 1 ===<br />
LPA<sub>1</sub> is also closely related to the first of the six [http://www.nature.com/ijo/journal/v30/n1s/full/0803272a.html cannabinoid receptors]. This close relation gives CB<sub>1</sub> ([[Cannabinoid Receptor 1]]) the ability to bind to analogs of LPA and LPA<sub>1</sub> the ability to bind to analogs of CB<sub>1</sub> ligands. <ref name="regpeps">PMID: 26091040</ref> This crossing over of ligand binding opens the possibility of metabolic crosstalk between the two signaling systems. <ref name="regpeps">PMID: 26091040</ref> Complementary access to the LPA<sub>1</sub> binding pocket can be achieved by phosphorylated CB<sub>1</sub> ligand analogs, while complementary access to the CB<sub>1</sub> binding site requires dephosphorylation of LPA<sub>1</sub> ligand analogs (Figure 4). In both cases, a ligand could serve as a primary [https://en.wikipedia.org/wiki/Selective_receptor_modulator receptor modulator] and a simultaneous [https://en.wikipedia.org/wiki/Prodrug prodrug] for a different receptor. <ref name="regpeps">PMID: 26091040</ref><br />
<br />
[[Image:Ligands-1.png|200 px|left|thumb|Figure 4: Respective ligands of LPA<sub>1</sub> and CB<sub>1</sub>. LPA binds to CB<sub>1</sub> after dephosphorylation, while 2-AG binds to LPA<sub>1</sub> after phosphorylation.]]<br />
<br />
<scene name='72/721543/Asp129_and_trp210/2'>Residues Asp129 and Trp210</scene> located within the hydrophobic binding pocket of LPA<sub>1</sub> may share responsibility for the preference for long unsaturated acyl chains, including the ligand LPA. The polarity of these residues provide favorable interactions between the ligand and the binding pocket.<ref name="regpeps">PMID: 26091040</ref> Additionally, Asp129 and Trp210 may serve as a trigger for agonist induced conformational changes. These residues are also interesting in regard to GPCR phylogenic evolution. <ref name="regpeps">PMID: 26091040</ref> Trp210 specifically only occurs in this position in 1% of all class A GPCR receptors and is unique to lysophospholipid and cannabinoid receptors. <ref name = 'Van Durme'>Van Durme, J., Horn, F., Costagliola, S., Vriend, G., and Vassart, G. “GRIS: glycoprotein-hormone receptor information system.” Mol. (2006) Endocrinol. 20, 2247-2255' </ref> A model for lipid agonist binding generated through molecular modeling was used to dock two of the cannabinoid receptor CB<sub>1</sub>'s most abundant endogenous ligands into the LPA<sub>1</sub> binding pocket. <ref name="regpeps">PMID: 26091040</ref> Rotameric shifts of Trp210 and Trp271 lead to the expansion of the binding pocket and the exposure of the π clouds of their indole rings. These shifts and expansion provided favorable interactions with the double bonds of the phosphorylated cannabinoid ligands (Figure 5). This favorable binding provided evidence that the hydrophobic binding pockets of LPA<sub>1</sub> and CB<sub>1</sub> are able to favorably bind the same poly-unsaturated acyl chains with metabolically interconvertible head groups. <ref name="regpeps">PMID: 26091040</ref><br />
[[Image:TrpRotamericShiftsCM.png|200 px|left|thumb|Figure 5: Illustration of key LPA<sub>1</sub> binding pocket residues Trp210 and Trp271. These residues provide rotameric shifts and expansion that allow for favorable interactions with phosphorylated cannabinoid ligands.]]<br />
<br />
== Disease Relevance ==<br />
Because LPA<sub>1</sub> is expressed in so many tissues throughout the body, LPA<sub>1</sub> has been linked to the symptoms and progression of several different diseases and disorders.<ref name="number6">PMID: 20331961</ref><ref name="number7">PMID: 24367336</ref> For example, due to LPA<sub>1</sub>'s role in pain signaling, overexpression of this protein can cause both [https://en.wikipedia.org/wiki/Allodynia allodynia] or [https://en.wikipedia.org/wiki/Hyperalgesia hyperalgesia], common symptoms of multiple sclerosis or strokes.<ref name="number6">PMID: 20331961</ref> In addition, since LPA<sub>1</sub> helps in the myelination of Schwann cells, mutation of the receptor can also lead to a decrease in [https://en.wikipedia.org/wiki/Prepulse_inhibition prepulse inhibition], a general sign of schizophrenia.<ref name="number6">PMID: 20331961</ref> Lastly, because of the mitogen signaling activity of LPA<sub>1</sub>, abnormal expression or mutation of this receptor has been linked to tumor growth, survival, and migration in both liver and lung tumors.<ref name="number7">PMID: 24367336</ref> Part of this tumorigenesis can be explained by the action of <scene name='72/721543/His40/4'>His40</scene> on LPA<sub>1</sub> where, when protonated, increases LPA binding affinity by up to 1kcal/mol.<ref name="regpeps">PMID: 26091040</ref> Consequently, in the acidic environment produced by [https://en.wikipedia.org/wiki/Tumor_hypoxia hypoxic tumors] creating lactic acid, LPA<sub>1</sub> activity is increased, allowing these tumors to continue to proliferate, migrate, and survive.<ref name="number7">PMID: 24367336</ref> In contrast, the LPA<sub>1</sub> receptor also induces protective functions in different cardiovascular conditions. For example, in patients with heart disease, LPA<sub>1</sub> communicates with [[PI3K]], [https://en.wikipedia.org/wiki/Protein_kinase_B PKB], and [[ERK]] to create a hypertrophic response in the heart to offset reduced heart contractions.<ref name="number6">PMID: 20331961</ref><br />
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</StructureSection><br />
== References ==<br />
<references/></div>Chandler Mitchellhttps://proteopedia.org/index.php?title=File:Ligands-1.png&diff=2587674File:Ligands-1.png2016-04-18T23:44:04Z<p>Chandler Mitchell: </p>
<hr />
<div></div>Chandler Mitchellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1172&diff=2587669Sandbox Reserved 11722016-04-18T23:05:05Z<p>Chandler Mitchell: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Central_Metabolism}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Lysophosphatidic Acid Receptor 1==<br />
<StructureSection load='4z34' size='340' side='right' caption='Cartoon representation of the LPA1 protein and its antagonist, ON7, colored in white. ([https://en.wikipedia.org/wiki/Protein_Data_Bank PDB] code [http://www.rcsb.org/pdb/explore/explore.do?structureId=4z34 4Z34]) ' scene='72/721543/Overallrainbow2/1'><br />
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<br />
== Introduction ==<br />
Lysophosphatidic Acid Receptor 1 (commonly referred to as LPA<sub>1</sub>) is a [[G protein-coupled receptor]] and one of 6 different LPA receptors (LPA<sub>1</sub>-LPA<sub>6</sub>). These receptors bind the phospholipid derivative [https://en.wikipedia.org/wiki/Lysophosphatidic_acid lysophosphatidic acid (LPA)], a signaling molecule that acts as a potent [https://en.wikipedia.org/wiki/Mitogen mitogen] upon binding to one of its six receptors.<ref name="regpeps">PMID: 26091040</ref> LPA<sub>1</sub> is part of the larger [http://jb.oxfordjournals.org/content/131/6/767 EDG receptor family], which includes the more widely studied sphingosine 1-phopshate receptors.<ref name="regpeps">PMID: 26091040</ref> This receptor is responsible for initiating several different signaling cascades with different molecules and G-proteins.<ref name = 'Yung'>Yung, Y. C., N. C. Stoddard, and J. Chun. "LPA Receptor Signaling: Pharmacology, Physiology, and Pathophysiology." The Journal of Lipid Research 55.7 (2014): 1192-214. Web. 17 Feb. 2016.' </ref> These cascades ultimately result in growth, survival, and movement of cells, as well as neural cell development.<ref name = 'Chun'>Chun, J., Hla, T., Spiegel, S., and Moolenaar, W.H. “Lysophospholipid Receptors: Signaling and Biochemistry.” John Wiley & Sons, Inc. (2013) pp.i-xviii. 5 Feb. 2016.' </ref><br />
== Structure ==<br />
[[Image:Pic2proteo3.png|275 px|left|thumb|Figure 1: Surface representation of the LPA<sub>1</sub> receptor in tan interacting with its antagonist, ON7, shown in green and red sticks.The exterior of the protein was partially cut away to display the interior binding pocket.]]<br />
The LPA<sub>1</sub> receptor protein is composed of 364 amino acids with a molecular weight of approximately 41 kDa. Common to all G-protein coupled receptors, LPA<sub>1</sub> contains seven [http://kinemage.biochem.duke.edu/teaching/anatax/html/anatax.2a.html alpha helices] which make up the seven transmembrane spanning domains with three intracellular loops and three extracellular loops.<ref name = 'Hernández-Méndez'>Hernández-Méndez, Aurelio, Rocío Alcántara-Hernández, and J. Adolfo García-Sáinz. "Lysophosphatidic Acid LPA1-3 Receptors: Signaling, Regulation and in Silico Analysis of Their Putative Phosphorylation Sites." Receptors & Clinical Investigation Receptor Clin Invest 1.3 (2014). Web. 15 Feb. 2016.' </ref> Within these helices is a binding pocket which stabilizes the binding of its ligand, LPA (Figure 1).<br />
=== Key Ligand Interactions ===<br />
[[Image:Amphbindingfinal.png|275 px|right|thumb|Figure 2: Electrostatic illustration of the amphipathic binding pocket of the LPA<sub>1</sub> receptor. This binding pocket was revealed by cutting away the exterior or the protein. This binding pocket, located in the interior of the protein, has both polar and nonpolar regions. The blue and red coloration highlight the positively and negatively charged regions, respectively, and the white color shows the nonpolar region of the binding pocket.]]<br />
The biological ligand of the LPA<sub>1</sub> receptor receptor is [https://en.wikipedia.org/wiki/Lysophosphatidic_acid lysophosphatidic acid (LPA)], a phospholipid that contains a long, nonpolar tail, a phosphate head, a chiral hydroxyl group, and an ester group. This receptor provides specificity for its ligand by the amphipathic binding pocket; the positive region on the left hand side of the pocket stabilizes the LPA's phosphate group, the nonpolar region at the bottom of the binding pocket stabilizes the hydrophobic tail of LPA, and the polar region at the top of the pocket stabilize binding of the ester and hydroxyl group (Figure 2). [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=8589 ONO-9780307 (ON7)] is an antagonist for LPA due to its large nonpolar region, chiral hydroxyl group, ester, and carboxylic acid which all resemble portions of the LPA molecule. Four separate interactions with this antagonist of LPA<sub>1</sub> help demonstrate the key interactions that stabilize the binding of the LPA phospholipid to this receptor. In the nonpolar region of the binding pocket, <scene name='72/721543/Nonpolar/2'>three non polar residues</scene> of LPA<sub>1</sub> stabilize the large nonpolar group of ON7. At the polar region, the ligand binding is stabilized by <scene name='72/721543/Arg124gln125/4'>Arg124 and Glu125</scene> forming ionic and polar interactions with the carboxylic acid and the hydroxyl group of ON7.<ref name="regpeps">PMID: 26091040</ref> In addition, interplay between <scene name='72/721543/Lys39_and_glu293/8'>Glu293 and Lys39</scene> causes another stabilizing component with the ON7 antagonist. Glu293 forms polar interactions with Lys39, positioning it in close proximity to to the carboxylic acid of ON7, which then interactions with Lys39 via ionic bonding.<ref name="regpeps">PMID: 26091040</ref> While Lys39 is highly conserved among all six LPA receptors, a neighboring histidine residue is specific to the LPA<sub>1</sub> receptor. <scene name='72/721543/His40/4'>His40</scene> forms both ionic and polar interactions with the carboxylic acid of ON7. Protonation of this residue greatly affects the binding affinity of LPA, leading to an increase in the pathways associated with cell proliferation and migration. Because cancerous tumors create acidic environments where His40 is protonated, this residue is an important link to tumor growth and cancer cell movement.<ref name="regpeps">PMID: 26091040</ref><br />
<br />
<br />
== Function ==<br />
The LPA<sub>1</sub> receptor is present in nearly all cells and tissues, and deletion of the LPA<sub>1</sub> receptor has physiological effects on every organ system, indicating its wide range of functions. Specifically, this receptor initiates downstream signaling cascades with three G<sub>α</sub> proteins: G<sub>i/o</sub>, G<sub>q/11</sub>, and G<sub>12/13</sub>. Specifically, G<sub>α</sub> proteins begin signaling cascades that activate [https://en.wikipedia.org/wiki/Phospholipase_C phospholipase C] and [[MAPK]]s that signal for cell proliferation, survival, and migration. <ref name = 'Yung'>Yung, Y. C., N. C. Stoddard, and J. Chun. "LPA Receptor Signaling: Pharmacology, Physiology, and Pathophysiology." The Journal of Lipid Research 55.7 (2014): 1192-214. Web. 17 Feb. 2016.' </ref> Despite this receptor being expressed ubiquitously, LPA<sub>1</sub> is highly expressed in neural tissue, aiding in several different neurodevelopmental processes including growth and folding of the [https://www.dartmouth.edu/~rswenson/NeuroSci/chapter_11.html cerebral cortex] and the growth, survival, and migration of neural [https://en.wikipedia.org/wiki/Progenitor_cell progenitor cells].<ref name = 'Chun'>Chun, J., Hla, T., Spiegel, S., and Moolenaar, W.H. “Lysophospholipid Receptors: Signaling and Biochemistry.” John Wiley & Sons, Inc. (2013) pp.i-xviii. 5 Feb. 2016.' </ref> Finally, LPA<sub>1</sub> receptors expressed in neural tissue act through a signaling pathway with the [https://en.wikipedia.org/wiki/RAC1 Rac1] G-protein to aid in Schwann cell migration and myelination.<ref name="number5">PMID: 24115248</ref><br />
<br />
<br />
<br />
== Receptor Comparison ==<br />
<br />
=== Sphingosine 1-Phosphate Receptor ===<br />
LPA<sub>1</sub> belongs to the EDG (endothelial differentiation gene) family of [https://en.wikipedia.org/wiki/Lysophospholipid_receptor lysophospholipid receptors]. This family also includes the [https://en.wikipedia.org/wiki/S1PR1 sphingosine 1-phosphate receptor 1] (S1P<sub>1</sub>), which shares many structural similarities to LPA<sub>1</sub>. In fact, the transmembrane regions share a sequence identity of 41%. <ref name = 'Chun, E.'>Chun, E., Thompson, A.A., Lui, W., Roth, C.B., Griffith, M.T., Katritch, V., Kunken, J., Xu, F., Cherezov, V., Hanson, M.A., and Stevens, R.C. “Fusion partner tool chest for the stabilization and crystallization of G protein-coupled receptors.” Structure 20, (2012) 967-976.' </ref> A defining difference between these two receptors is their mode of ligand access to the binding site. The hydrophobic [https://en.wikipedia.org/wiki/Sphingosine-1-phosphate S1P ligand] enters S1P<sub>1</sub> via the membrane. LPA<sub>1</sub> differs and utilizes an extracellular opening that allows LPA access from the extracellular space (Figure 3). <ref name="regpeps">PMID: 26091040</ref> Structural evidence for this altered ligand binding pathway includes global changes in the positioning of the extracellular loops (ECL) and transmembrane helices (TM). Specifically, a slight divergence of <scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene>, which is positioned 3 Å closer to TMVII compared to S1P<sub>1</sub>, and a repositioning of <scene name='72/721543/Ecl_regions/1'>ECL3</scene>, resulting in a divergence of 8 Å from S1P<sub>1</sub> result in ligand access via the extracellular space. <ref name="regpeps">PMID: 26091040</ref> This narrowing of the gap between TMI and TMVII blocks membrane ligand access in LPA<sub>1</sub>, while the greater distance between ECL3 and the other extracellular loops promotes extracellular access for LPA<sub>1</sub>. Additionally, ECL0 is helical in S1P<sub>1</sub>, but <scene name='72/721543/Ecl02ndstructure/1'>lacks secondary structure</scene> in LPA<sub>1</sub>. This increased flexibility that results from ECL0 lack of secondary structure in LPA<sub>1</sub> further promotes favorable LPA access to the binding pocket from the extracellular space. <ref name="regpeps">PMID: 26091040</ref><br />
<br />
<br />
[[Image:ECL3DistanceCM.png|200 px|left|thumb|Figure 3: Extracellular ligand access pathway on LPA<sub>1</sub>. Compared to S1P<sub>1</sub>, ECL3 shown in red is positioned 8 Å further from ECL0 and ECL2 shown in green. This largely contributes to the altered ligand binding pathway between LPA<sub>1</sub>, and S1P<sub>1</sub>]]<br />
<br />
=== Endocannabinoid Receptor 1 ===<br />
LPA<sub>1</sub> is also closely related to the first of the six [http://www.nature.com/ijo/journal/v30/n1s/full/0803272a.html cannabinoid receptors]. This close relation gives CB<sub>1</sub> ([[Cannabinoid Receptor 1]]) the ability to bind to analogs of LPA and LPA<sub>1</sub> the ability to bind to analogs of CB<sub>1</sub> ligands. <ref name="regpeps">PMID: 26091040</ref> This crossing over of ligand binding opens the possibility of metabolic crosstalk between the two signaling systems. This connection is made possible through ligand phosphorylation and dephosphorylation. <ref name="regpeps">PMID: 26091040</ref> Specifically, complementary access to the LPA<sub>1</sub> binding pocket can be achieved by phosphorylated CB<sub>1</sub> ligand analogs, while complementary access to the CB<sub>1</sub> binding site requires dephosphorylation of LPA<sub>1</sub> ligand analogs. In both cases, a ligand could serve as a primary [https://en.wikipedia.org/wiki/Selective_receptor_modulator receptor modulator] and a simultaneous [https://en.wikipedia.org/wiki/Prodrug prodrug] for a different receptor. <ref name="regpeps">PMID: 26091040</ref><br />
<br />
<scene name='72/721543/Asp129_and_trp210/2'>Residues Asp129 and Trp210</scene> located within the hydrophobic binding pocket of LPA<sub>1</sub> may share responsibility for the preference for long unsaturated acyl chains. These residues are also interesting in regard to GPCR phylogenic evolution. <ref name="regpeps">PMID: 26091040</ref> Trp210 specifically only occurs in this position in 1% of all class A GPCR receptors and is unique to lysophospholipid and cannabinoid receptors. <ref name = 'Van Durme'>Van Durme, J., Horn, F., Costagliola, S., Vriend, G., and Vassart, G. “GRIS: glycoprotein-hormone receptor information system.” Mol. (2006) Endocrinol. 20, 2247-2255' </ref> A model for lipid agonist binding generated through molecular modeling was used to dock two of the cannabinoid receptor CB<sub>1</sub>'s most abundant endogenous ligands into the LPA<sub>1</sub> binding pocket. <ref name="regpeps">PMID: 26091040</ref> Rotameric shifts of Trp210 and Trp271 lead to the expansion of the binding pocket and the exposure of the π clouds of their indole rings. These shifts and expansion provided favorable interactions with the double bonds of the phosphorylated cannabinoid ligands (Figure 4). This favorable binding provided evidence that the hydrophobic binding pockets of LPA<sub>1</sub> and CB<sub>1</sub> are able to favorably bind the same poly-unsaturated acyl chains with metabolically interconvertible head groups. <ref name="regpeps">PMID: 26091040</ref><br />
[[Image:TrpRotamericShiftsCM.png|200 px|left|thumb|Figure 4: Illustration of key LPA<sub>1</sub> binding pocket residues Trp210 and Trp271. These residues provide rotameric shifts and expansion that allow for favorable interactions with phosphorylated cannabinoid ligands.]]<br />
<br />
== Disease Relevance ==<br />
Because LPA<sub>1</sub> is expressed in so many tissues throughout the body, LPA<sub>1</sub> has been linked to the symptoms and progression of several different diseases and disorders.<ref name="number6">PMID: 20331961</ref><ref name="number7">PMID: 24367336</ref> For example, due to LPA<sub>1</sub>'s role in pain signaling, overexpression of this protein can cause both [https://en.wikipedia.org/wiki/Allodynia allodynia] or [https://en.wikipedia.org/wiki/Hyperalgesia hyperalgesia], common symptoms of multiple sclerosis or strokes.<ref name="number6">PMID: 20331961</ref> In addition, since LPA<sub>1</sub> helps in the myelination of Schwann cells, mutation of the receptor can also lead to a decrease in [https://en.wikipedia.org/wiki/Prepulse_inhibition prepulse inhibition], a general sign of schizophrenia.<ref name="number6">PMID: 20331961</ref> Lastly, because of the mitogen signaling activity of LPA<sub>1</sub>, abnormal expression or mutation of this receptor has been linked to tumor growth, survival, and migration in both liver and lung tumors.<ref name="number7">PMID: 24367336</ref> Part of this tumorigenesis can be explained by the action of <scene name='72/721543/His40/4'>His40</scene> on LPA<sub>1</sub> where, when protonated, increases LPA binding affinity by up to 1kcal/mol.<ref name="regpeps">PMID: 26091040</ref> Consequently, in the acidic environment produced by [https://en.wikipedia.org/wiki/Tumor_hypoxia hypoxic tumors] creating lactic acid, LPA<sub>1</sub> activity is increased, allowing these tumors to continue to proliferate, migrate, and survive.<ref name="number7">PMID: 24367336</ref> In contrast, the LPA<sub>1</sub> receptor also induces protective functions in different cardiovascular conditions. For example, in patients with heart disease, LPA<sub>1</sub> communicates with [[PI3K]], [https://en.wikipedia.org/wiki/Protein_kinase_B PKB], and [[ERK]] to create a hypertrophic response in the heart to offset reduced heart contractions.<ref name="number6">PMID: 20331961</ref><br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Chandler Mitchellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1172&diff=2587661Sandbox Reserved 11722016-04-18T22:30:02Z<p>Chandler Mitchell: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Central_Metabolism}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Lysophosphatidic Acid Receptor 1==<br />
<StructureSection load='4z34' size='340' side='right' caption='Cartoon representation of the LPA1 protein and its antagonist, ON7, colored in white. ([https://en.wikipedia.org/wiki/Protein_Data_Bank PDB] code [http://www.rcsb.org/pdb/explore/explore.do?structureId=4z34 4Z34]) ' scene='72/721543/Overallrainbow2/1'><br />
<br />
<br />
== Introduction ==<br />
Lysophosphatidic Acid Receptor 1 (commonly referred to as LPA<sub>1</sub>) is a [[G protein-coupled receptor]] and one of 6 different LPA receptors (LPA<sub>1</sub>-LPA<sub>6</sub>). These receptors bind the phospholipid derivative [https://en.wikipedia.org/wiki/Lysophosphatidic_acid lysophosphatidic acid (LPA)], a signaling molecule that acts as a potent [https://en.wikipedia.org/wiki/Mitogen mitogen] upon binding to one of its six receptors.<ref name="regpeps">PMID: 26091040</ref> LPA<sub>1</sub> is part of the larger [http://jb.oxfordjournals.org/content/131/6/767 EDG receptor family], which includes the more widely studied sphingosine 1-phopshate receptors.<ref name="regpeps">PMID: 26091040</ref> This receptor is responsible for initiating several different signaling cascades with different molecules and G-proteins.<ref name = 'Yung'>Yung, Y. C., N. C. Stoddard, and J. Chun. "LPA Receptor Signaling: Pharmacology, Physiology, and Pathophysiology." The Journal of Lipid Research 55.7 (2014): 1192-214. Web. 17 Feb. 2016.' </ref> These cascades ultimately result in growth, survival, and movement of cells, as well as neural cell development.<ref name = 'Chun'>Chun, J., Hla, T., Spiegel, S., and Moolenaar, W.H. “Lysophospholipid Receptors: Signaling and Biochemistry.” John Wiley & Sons, Inc. (2013) pp.i-xviii. 5 Feb. 2016.' </ref><br />
== Structure ==<br />
[[Image:Pic2proteo3.png|275 px|left|thumb|Figure 1: Surface representation of the LPA<sub>1</sub> receptor in tan interacting with its antagonist, ON7, shown in green and red sticks.The exterior of the protein was partially cut away to display the interior binding pocket.]]<br />
The LPA<sub>1</sub> receptor protein is composed of 364 amino acids with a molecular weight of approximately 41 kDa. Common to all G-protein coupled receptors, LPA<sub>1</sub> contains seven [http://kinemage.biochem.duke.edu/teaching/anatax/html/anatax.2a.html alpha helices] which make up the seven transmembrane spanning domains with three intracellular loops and three extracellular loops.<ref name = 'Hernández-Méndez'>Hernández-Méndez, Aurelio, Rocío Alcántara-Hernández, and J. Adolfo García-Sáinz. "Lysophosphatidic Acid LPA1-3 Receptors: Signaling, Regulation and in Silico Analysis of Their Putative Phosphorylation Sites." Receptors & Clinical Investigation Receptor Clin Invest 1.3 (2014). Web. 15 Feb. 2016.' </ref> Within these helices is a binding pocket which stabilizes the binding of its ligand, LPA (Figure 1).<br />
=== Key Ligand Interactions ===<br />
[[Image:Amphbindingfinal.png|275 px|right|thumb|Figure 2: Electrostatic illustration of the amphipathic binding pocket of the LPA<sub>1</sub> receptor. This binding pocket was revealed by cutting away the exterior or the protein. This binding pocket, located in the interior of the protein, has both polar and nonpolar regions. The blue and red coloration highlight the positively and negatively charged regions, respectively, and the white color shows the nonpolar region of the binding pocket.]]<br />
The biological ligand of the LPA<sub>1</sub> receptor receptor is [https://en.wikipedia.org/wiki/Lysophosphatidic_acid lysophosphatidic acid (LPA)], a phospholipid that contains a long, nonpolar tail, a phosphate head, a chiral hydroxyl group, and an ester group. This receptor provides specificity for its ligand by the amphipathic binding pocket; the positive region on the left hand side of the pocket stabilizes the LPA's phosphate group, the nonpolar region at the bottom of the binding pocket stabilizes the hydrophobic tail of LPA, and the polar region at the top of the pocket stabilize binding of the ester and hydroxyl group (Figure 2). [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=8589 ONO-9780307 (ON7)] is an antagonist for LPA due to its large nonpolar region, chiral hydroxyl group, ester, and carboxylic acid which all resemble portions of the LPA molecule. Four separate interactions with this antagonist of LPA<sub>1</sub> help demonstrate the key interactions that stabilize the binding of the LPA phospholipid to this receptor. In the nonpolar region of the binding pocket, <scene name='72/721543/Nonpolar/2'>three non polar residues</scene> of LPA<sub>1</sub> stabilize the large nonpolar group of ON7. At the polar region, the ligand binding is stabilized by <scene name='72/721543/Arg124gln125/4'>Arg124 and Glu125</scene> forming ionic and polar interactions with the carboxylic acid and the hydroxyl group of ON7.<ref name="regpeps">PMID: 26091040</ref> In addition, interplay between <scene name='72/721543/Lys39_and_glu293/8'>Glu293 and Lys39</scene> causes another stabilizing component with the ON7 antagonist. Glu293 forms polar interactions with Lys39, positioning it in close proximity to to the carboxylic acid of ON7, which then interactions with Lys39 via ionic bonding.<ref name="regpeps">PMID: 26091040</ref> While Lys39 is highly conserved among all six LPA receptors, a neighboring histidine residue is specific to the LPA<sub>1</sub> receptor. <scene name='72/721543/His40/4'>His40</scene> forms both ionic and polar interactions with the carboxylic acid of ON7. Protonation of this residue greatly affects the binding affinity of LPA, leading to an increase in the pathways associated with cell proliferation and migration. Because cancerous tumors create acidic environments where His40 is protonated, this residue is an important link to tumor growth and cancer cell movement.<ref name="regpeps">PMID: 26091040</ref><br />
<br />
<br />
== Function ==<br />
The LPA<sub>1</sub> receptor is present in nearly all cells and tissues, and deletion of the LPA<sub>1</sub> receptor has physiological effects on every organ system, indicating its wide range of functions. Specifically, this receptor initiates downstream signaling cascades with three G<sub>α</sub> proteins: G<sub>i/o</sub>, G<sub>q/11</sub>, and G<sub>12/13</sub>. Specifically, G<sub>α</sub> proteins begin signaling cascades that activate [https://en.wikipedia.org/wiki/Phospholipase_C phospholipase C] and [[MAPK]]s that signal for cell proliferation, survival, and migration. <ref name = 'Yung'>Yung, Y. C., N. C. Stoddard, and J. Chun. "LPA Receptor Signaling: Pharmacology, Physiology, and Pathophysiology." The Journal of Lipid Research 55.7 (2014): 1192-214. Web. 17 Feb. 2016.' </ref> Despite this receptor being expressed ubiquitously, LPA<sub>1</sub> is highly expressed in neural tissue, aiding in several different neurodevelopmental processes including growth and folding of the [https://www.dartmouth.edu/~rswenson/NeuroSci/chapter_11.html cerebral cortex] and the growth, survival, and migration of neural [https://en.wikipedia.org/wiki/Progenitor_cell progenitor cells].<ref name = 'Chun'>Chun, J., Hla, T., Spiegel, S., and Moolenaar, W.H. “Lysophospholipid Receptors: Signaling and Biochemistry.” John Wiley & Sons, Inc. (2013) pp.i-xviii. 5 Feb. 2016.' </ref> Finally, LPA<sub>1</sub> receptors expressed in neural tissue act through a signaling pathway with the [https://en.wikipedia.org/wiki/RAC1 Rac1] G-protein to aid in Schwann cell migration and myelination.<ref name="number5">PMID: 24115248</ref><br />
<br />
<br />
<br />
== Receptor Comparison ==<br />
<br />
=== Sphingosine 1-Phosphate Receptor ===<br />
LPA<sub>1</sub> belongs to the EDG (endothelial differentiation gene) family of [https://en.wikipedia.org/wiki/Lysophospholipid_receptor lysophospholipid receptors]. This family also includes the [https://en.wikipedia.org/wiki/S1PR1 sphingosine 1-phosphate receptor 1] (S1P<sub>1</sub>), which shares many structural similarities to LPA<sub>1</sub>. In fact, the transmembrane regions share a sequence identity of 41%. <ref name = 'Chun, E.'>Chun, E., Thompson, A.A., Lui, W., Roth, C.B., Griffith, M.T., Katritch, V., Kunken, J., Xu, F., Cherezov, V., Hanson, M.A., and Stevens, R.C. “Fusion partner tool chest for the stabilization and crystallization of G protein-coupled receptors.” Structure 20, (2012) 967-976.' </ref> A defining difference between these two receptors is their mode of ligand access to the binding site. The hydrophobic [https://en.wikipedia.org/wiki/Sphingosine-1-phosphate S1P ligand] enters S1P<sub>1</sub> via the membrane. LPA<sub>1</sub> differs and utilizes an extracellular opening that allows LPA access from the extracellular space (Figure 3). <ref name="regpeps">PMID: 26091040</ref> Structural evidence for this altered ligand binding pathway includes global changes in the positioning of the extracellular loops (ECL) and transmembrane helices (TM). Specifically, a slight divergence of <scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene>, which is positioned 3 Å closer to TMVII compared to S1P<sub>1</sub>, and a repositioning of <scene name='72/721543/Ecl_regions/1'>ECL3</scene>, resulting in a divergence of 8 Å from S1P<sub>1</sub> result in ligand access via the extracellular space. <ref name="regpeps">PMID: 26091040</ref> This narrowing of the gap between TMI and TMVII blocks membrane ligand access, while the greater distance between ECL3 and the other extracellular loops promotes extracellular access for LPA<sub>1</sub>. Additionally, ECL0 is helical in S1P<sub>1</sub>, but <scene name='72/721543/Ecl02ndstructure/1'>lacks secondary structure</scene> in LPA<sub>1</sub>. This increased flexibility that results further promotes favorable access from the extracellular space. <ref name="regpeps">PMID: 26091040</ref><br />
<br />
<br />
[[Image:ECL3DistanceCM.png|200 px|left|thumb|Figure 3: Extracellular ligand access pathway on LPA<sub>1</sub>. Compared to S1P<sub>1</sub>, ECL3 shown in red is positioned 8 Å further from ECL0 and ECL2 shown in green. This largely contributes to the altered ligand binding pathway between LPA<sub>1</sub>, and S1P<sub>1</sub>]]<br />
<br />
=== Endocannabinoid Receptor 1 ===<br />
LPA<sub>1</sub> also is closely related to the first of the [http://www.nature.com/ijo/journal/v30/n1s/full/0803272a.html cannabinoid receptors]. This close relation gives CB<sub>1</sub> ([[Cannabinoid Receptor 1]]) the ability to bind to analogs of LPA and vice versa, which opens the possibility of metabolic crosstalk between the two signaling systems. This connection is made possible through ligand phosphorylation and dephosphorylation. <ref name="regpeps">PMID: 26091040</ref> Specifically, complementary access to the LPA<sub>1</sub> binding pocket can be achieved by phosphorylated CB<sub>1</sub> ligand analogs, while complementary access to the CB<sub>1</sub> binding site requires dephosphorylation of LPA<sub>1</sub> ligand analogs. In both cases, a ligand could serve as a primary [https://en.wikipedia.org/wiki/Selective_receptor_modulator receptor modulator] and a simultaneous [https://en.wikipedia.org/wiki/Prodrug prodrug] for a different receptor. <ref name="regpeps">PMID: 26091040</ref><br />
<br />
<scene name='72/721543/Asp129_and_trp210/2'>Residues Asp129 and Trp210</scene> located within the hydrophobic binding pocket of LPA<sub>1</sub> may share responsibility for the preference for long unsaturated acyl chains. These residues are also interesting in regard to GPCR phylogenic evolution. <ref name="regpeps">PMID: 26091040</ref> Trp210 specifically only occurs in this position in 1% of all class A GPCR receptors and is unique to lysophospholipid and cannabinoid receptors. <ref name = 'Van Durme'>Van Durme, J., Horn, F., Costagliola, S., Vriend, G., and Vassart, G. “GRIS: glycoprotein-hormone receptor information system.” Mol. (2006) Endocrinol. 20, 2247-2255' </ref><br />
<br />
A model for lipid agonist binding generated through molecular modeling was used to dock two of the cannabinoid receptor CB<sub>1</sub>'s most abundant endogenous ligands into the LPA<sub>1</sub> binding pocket. <ref name="regpeps">PMID: 26091040</ref> Rotameric shifts of Trp210 and Trp271 leading to expansion of the binding pocket and the exposure of the π clouds of their indole rings provided favorable interactions with the double bonds of the phosphorylated cannabinoid ligands (Figure 4). This favorable binding provides evidence that the hydrophobic binding pockets of LPA<sub>1</sub> and CB<sub>1</sub> are able to favorably bind the same poly-unsaturated acyl chains with metabolically interconvertible head groups. <ref name="regpeps">PMID: 26091040</ref><br />
[[Image:TrpRotamericShiftsCM.png|200 px|left|thumb|Figure 4: Illustration of key LPA<sub>1</sub> binding pocket residues Trp210 and Trp271. These residues provide rotameric shifts and expansion that allow for favorable interactions with phosphorylated cannabinoid ligands.]]<br />
<br />
== Disease Relevance ==<br />
Because LPA<sub>1</sub> is expressed in so many tissues throughout the body, LPA<sub>1</sub> has been linked to the symptoms and progression of several different diseases and disorders.<ref name="number6">PMID: 20331961</ref><ref name="number7">PMID: 24367336</ref> For example, due to LPA<sub>1</sub>'s role in pain signaling, overexpression of this protein can cause both [https://en.wikipedia.org/wiki/Allodynia allodynia] or [https://en.wikipedia.org/wiki/Hyperalgesia hyperalgesia], common symptoms of multiple sclerosis or strokes.<ref name="number6">PMID: 20331961</ref> In addition, since LPA<sub>1</sub> helps in the myelination of Schwann cells, mutation of the receptor can also lead to a decrease in [https://en.wikipedia.org/wiki/Prepulse_inhibition prepulse inhibition], a general sign of schizophrenia.<ref name="number6">PMID: 20331961</ref> Lastly, because of the mitogen signaling activity of LPA<sub>1</sub>, abnormal expression or mutation of this receptor has been linked to tumor growth, survival, and migration in both liver and lung tumors.<ref name="number7">PMID: 24367336</ref> Part of this tumorigenesis can be explained by the action of <scene name='72/721543/His40/4'>His40</scene> on LPA<sub>1</sub> where, when protonated, increases LPA binding affinity by up to 1kcal/mol.<ref name="regpeps">PMID: 26091040</ref> Consequently, in the acidic environment produced by [https://en.wikipedia.org/wiki/Tumor_hypoxia hypoxic tumors] creating lactic acid, LPA<sub>1</sub> activity is increased, allowing these tumors to continue to proliferate, migrate, and survive.<ref name="number7">PMID: 24367336</ref> In contrast, the LPA<sub>1</sub> receptor also induces protective functions in different cardiovascular conditions. For example, in patients with heart disease, LPA<sub>1</sub> communicates with [[PI3K]], [https://en.wikipedia.org/wiki/Protein_kinase_B PKB], and [[ERK]] to create a hypertrophic response in the heart to offset reduced heart contractions.<ref name="number6">PMID: 20331961</ref><br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Chandler Mitchellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1172&diff=2587660Sandbox Reserved 11722016-04-18T22:26:55Z<p>Chandler Mitchell: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Central_Metabolism}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Lysophosphatidic Acid Receptor 1==<br />
<StructureSection load='4z34' size='340' side='right' caption='Cartoon representation of the LPA1 protein and its antagonist, ON7, colored in white. ([https://en.wikipedia.org/wiki/Protein_Data_Bank PDB] code [http://www.rcsb.org/pdb/explore/explore.do?structureId=4z34 4Z34]) ' scene='72/721543/Overallrainbow2/1'><br />
<br />
<br />
== Introduction ==<br />
Lysophosphatidic Acid Receptor 1 (commonly referred to as LPA<sub>1</sub>) is a [[G protein-coupled receptor]] and one of 6 different LPA receptors (LPA<sub>1</sub>-LPA<sub>6</sub>). These receptors bind the phospholipid derivative [https://en.wikipedia.org/wiki/Lysophosphatidic_acid lysophosphatidic acid (LPA)], a signaling molecule that acts as a potent [https://en.wikipedia.org/wiki/Mitogen mitogen] upon binding to one of its six receptors.<ref name="regpeps">PMID: 26091040</ref> LPA<sub>1</sub> is part of the larger [http://jb.oxfordjournals.org/content/131/6/767 EDG receptor family], which includes the more widely studied sphingosine 1-phopshate receptors.<ref name="regpeps">PMID: 26091040</ref> This receptor is responsible for initiating several different signaling cascades with different molecules and G-proteins.<ref name = 'Yung'>Yung, Y. C., N. C. Stoddard, and J. Chun. "LPA Receptor Signaling: Pharmacology, Physiology, and Pathophysiology." The Journal of Lipid Research 55.7 (2014): 1192-214. Web. 17 Feb. 2016.' </ref> These cascades ultimately result in growth, survival, and movement of cells, as well as neural cell development.<ref name = 'Chun'>Chun, J., Hla, T., Spiegel, S., and Moolenaar, W.H. “Lysophospholipid Receptors: Signaling and Biochemistry.” John Wiley & Sons, Inc. (2013) pp.i-xviii. 5 Feb. 2016.' </ref><br />
== Structure ==<br />
[[Image:Pic2proteo3.png|275 px|left|thumb|Figure 1: Surface representation of the LPA<sub>1</sub> receptor in tan interacting with its antagonist, ON7, shown in green and red sticks.The exterior of the protein was partially cut away to display the interior binding pocket.]]<br />
The LPA<sub>1</sub> receptor protein is composed of 364 amino acids with a molecular weight of approximately 41 kDa. Common to all G-protein coupled receptors, LPA<sub>1</sub> contains seven [http://kinemage.biochem.duke.edu/teaching/anatax/html/anatax.2a.html alpha helices] which make up the seven transmembrane spanning domains with three intracellular loops and three extracellular loops.<ref name = 'Hernández-Méndez'>Hernández-Méndez, Aurelio, Rocío Alcántara-Hernández, and J. Adolfo García-Sáinz. "Lysophosphatidic Acid LPA1-3 Receptors: Signaling, Regulation and in Silico Analysis of Their Putative Phosphorylation Sites." Receptors & Clinical Investigation Receptor Clin Invest 1.3 (2014). Web. 15 Feb. 2016.' </ref> Within these helices is a binding pocket which stabilizes the binding of its ligand, LPA (Figure 1).<br />
=== Key Ligand Interactions ===<br />
[[Image:Amphbindingfinal.png|275 px|right|thumb|Figure 2: Electrostatic illustration of the amphipathic binding pocket of the LPA<sub>1</sub> receptor. This binding pocket was revealed by cutting away the exterior or the protein. This binding pocket, located in the interior of the protein, has both polar and nonpolar regions. The blue and red coloration highlight the positively and negatively charged regions, respectively, and the white color shows the nonpolar region of the binding pocket.]]<br />
The biological ligand of the LPA<sub>1</sub> receptor receptor is [https://en.wikipedia.org/wiki/Lysophosphatidic_acid lysophosphatidic acid (LPA)], a phospholipid that contains a long, nonpolar tail, a phosphate head, a chiral hydroxyl group, and an ester group. This receptor provides specificity for its ligand by the amphipathic binding pocket; the positive region on the left hand side of the pocket stabilizes the LPA's phosphate group, the nonpolar region at the bottom of the binding pocket stabilizes the hydrophobic tail of LPA, and the polar region at the top of the pocket stabilize binding of the ester and hydroxyl group (Figure 2). [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=8589 ONO-9780307 (ON7)] is an antagonist for LPA due to its large nonpolar region, chiral hydroxyl group, ester, and carboxylic acid which all resemble portions of the LPA molecule. Four separate interactions with this antagonist of LPA<sub>1</sub> help demonstrate the key interactions that stabilize the binding of the LPA phospholipid to this receptor. In the nonpolar region of the binding pocket, <scene name='72/721543/Nonpolar/2'>three non polar residues</scene> of LPA<sub>1</sub> stabilize the large nonpolar group of ON7. At the polar region, the ligand binding is stabilized by <scene name='72/721543/Arg124gln125/4'>Arg124 and Glu125</scene> forming ionic and polar interactions with the carboxylic acid and the hydroxyl group of ON7.<ref name="regpeps">PMID: 26091040</ref> In addition, interplay between <scene name='72/721543/Lys39_and_glu293/8'>Glu293 and Lys39</scene> causes another stabilizing component with the ON7 antagonist. Glu293 forms polar interactions with Lys39, positioning it in close proximity to to the carboxylic acid of ON7, which then interactions with Lys39 via ionic bonding.<ref name="regpeps">PMID: 26091040</ref> While Lys39 is highly conserved among all six LPA receptors, a neighboring histidine residue is specific to the LPA<sub>1</sub> receptor. <scene name='72/721543/His40/4'>His40</scene> forms both ionic and polar interactions with the carboxylic acid of ON7. Protonation of this residue greatly affects the binding affinity of LPA, leading to an increase in the pathways associated with cell proliferation and migration. Because cancerous tumors create acidic environments where His40 is protonated, this residue is an important link to tumor growth and cancer cell movement.<ref name="regpeps">PMID: 26091040</ref><br />
<br />
<br />
== Function ==<br />
The LPA<sub>1</sub> receptor is present in nearly all cells and tissues, and deletion of the LPA<sub>1</sub> receptor has physiological effects on every organ system, indicating its wide range of functions. Specifically, this receptor initiates downstream signaling cascades with three G<sub>α</sub> proteins: G<sub>i/o</sub>, G<sub>q/11</sub>, and G<sub>12/13</sub>. Specifically, G<sub>α</sub> proteins begin signaling cascades that activate [https://en.wikipedia.org/wiki/Phospholipase_C phospholipase C] and [[MAPK]]s that signal for cell proliferation, survival, and migration. <ref name = 'Yung'>Yung, Y. C., N. C. Stoddard, and J. Chun. "LPA Receptor Signaling: Pharmacology, Physiology, and Pathophysiology." The Journal of Lipid Research 55.7 (2014): 1192-214. Web. 17 Feb. 2016.' </ref> Despite this receptor being expressed ubiquitously, LPA<sub>1</sub> is highly expressed in neural tissue, aiding in several different neurodevelopmental processes including growth and folding of the [https://www.dartmouth.edu/~rswenson/NeuroSci/chapter_11.html cerebral cortex] and the growth, survival, and migration of neural [https://en.wikipedia.org/wiki/Progenitor_cell progenitor cells].<ref name = 'Chun'>Chun, J., Hla, T., Spiegel, S., and Moolenaar, W.H. “Lysophospholipid Receptors: Signaling and Biochemistry.” John Wiley & Sons, Inc. (2013) pp.i-xviii. 5 Feb. 2016.' </ref> Finally, LPA<sub>1</sub> receptors expressed in neural tissue act through a signaling pathway with the [https://en.wikipedia.org/wiki/RAC1 Rac1] G-protein to aid in Schwann cell migration and myelination.<ref name="number5">PMID: 24115248</ref><br />
<br />
<br />
<br />
== Receptor Comparison ==<br />
<br />
=== Sphingosine 1-Phosphate Receptor ===<br />
LPA<sub>1</sub> belongs to the EDG (endothelial differentiation gene) family of [https://en.wikipedia.org/wiki/Lysophospholipid_receptor lysophospholipid receptors]. This family also includes the [https://en.wikipedia.org/wiki/S1PR1 sphingosine 1-phosphate receptor 1] (S1P<sub>1</sub>), which shares many structural similarities to LPA<sub>1</sub>. In fact, the transmembrane regions share a sequence identity of 41%. <ref name = 'Chun, E.'>Chun, E., Thompson, A.A., Lui, W., Roth, C.B., Griffith, M.T., Katritch, V., Kunken, J., Xu, F., Cherezov, V., Hanson, M.A., and Stevens, R.C. “Fusion partner tool chest for the stabilization and crystallization of G protein-coupled receptors.” Structure 20, (2012) 967-976.' </ref> A defining difference between these two receptors is their mode of ligand access to the binding site. The hydrophobic [https://en.wikipedia.org/wiki/Sphingosine-1-phosphate S1P ligand] enters S1P<sub>1</sub> via the membrane. LPA<sub>1</sub> differs and utilizes an extracellular opening that allows LPA access from the extracellular space (Figure 2). <ref name="regpeps">PMID: 26091040</ref> Structural evidence for this altered ligand binding pathway includes global changes in the positioning of the extracellular loops (ECL) and transmembrane helices (TM). Specifically, a slight divergence of <scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene>, which is positioned 3 Å closer to TMVII compared to S1P<sub>1</sub>, and a repositioning of <scene name='72/721543/Ecl_regions/1'>ECL3</scene>, resulting in a divergence of 8 Å from S1P<sub>1</sub> result in ligand access via the extracellular space. <ref name="regpeps">PMID: 26091040</ref> This narrowing of the gap between TMI and TMVII blocks membrane ligand access, while the greater distance between ECL3 and the other extracellular loops promotes extracellular access for LPA<sub>1</sub>. Additionally, ECL0 is helical in S1P<sub>1</sub>, but <scene name='72/721543/Ecl02ndstructure/1'>lacks secondary structure</scene> in LPA<sub>1</sub>. This increased flexibility that results further promotes favorable access from the extracellular space. <ref name="regpeps">PMID: 26091040</ref><br />
<br />
<br />
[[Image:ECL3DistanceCM.png|200 px|left|thumb|Figure 1: Extracellular ligand access pathway on LPA<sub>1</sub>. Compared to S1P<sub>1</sub>, ECL3 shown in red is positioned 8 Å further from ECL0 and ECL2 shown in green. This largely contributes to the altered ligand binding pathway between LPA<sub>1</sub>, and S1P<sub>1</sub>]]<br />
<br />
=== Endocannabinoid Receptor 1 ===<br />
LPA<sub>1</sub> also is closely related to the first of the [http://www.nature.com/ijo/journal/v30/n1s/full/0803272a.html cannabinoid receptors]. This close relation gives CB<sub>1</sub> ([[Cannabinoid Receptor 1]]) the ability to bind to analogs of LPA and vice versa, which opens the possibility of metabolic crosstalk between the two signaling systems. This connection is made possible through ligand phosphorylation and dephosphorylation. <ref name="regpeps">PMID: 26091040</ref> Specifically, complementary access to the LPA<sub>1</sub> binding pocket can be achieved by phosphorylated CB<sub>1</sub> ligand analogs, while complementary access to the CB<sub>1</sub> binding site requires dephosphorylation of LPA<sub>1</sub> ligand analogs. In both cases, a ligand could serve as a primary [https://en.wikipedia.org/wiki/Selective_receptor_modulator receptor modulator] and a simultaneous [https://en.wikipedia.org/wiki/Prodrug prodrug] for a different receptor. <ref name="regpeps">PMID: 26091040</ref><br />
<br />
<scene name='72/721543/Asp129_and_trp210/2'>Residues Asp129 and Trp210</scene> located within the hydrophobic binding pocket of LPA<sub>1</sub> may share responsibility for the preference for long unsaturated acyl chains. These residues are also interesting in regard to GPCR phylogenic evolution. <ref name="regpeps">PMID: 26091040</ref> Trp210 specifically only occurs in this position in 1% of all class A GPCR receptors and is unique to lysophospholipid and cannabinoid receptors. <ref name = 'Van Durme'>Van Durme, J., Horn, F., Costagliola, S., Vriend, G., and Vassart, G. “GRIS: glycoprotein-hormone receptor information system.” Mol. (2006) Endocrinol. 20, 2247-2255' </ref><br />
<br />
A model for lipid agonist binding generated through molecular modeling was used to dock two of the cannabinoid receptor CB<sub>1</sub>'s most abundant endogenous ligands into the LPA<sub>1</sub> binding pocket. <ref name="regpeps">PMID: 26091040</ref> Rotameric shifts of Trp210 and Trp271 leading to expansion of the binding pocket and the exposure of the π clouds of their indole rings provided favorable interactions with the double bonds of the phosphorylated cannabinoid ligands. This favorable binding provides evidence that the hydrophobic binding pockets of LPA<sub>1</sub> and CB<sub>1</sub> are able to favorably bind the same poly-unsaturated acyl chains with metabolically interconvertible head groups. <ref name="regpeps">PMID: 26091040</ref><br />
[[Image:TrpRotamericShiftsCM.png|200 px|left|thumb|Figure 1: Illustration of key LPA<sub>1</sub> binding pocket residues Trp210 and Trp271. These residues provide rotameric shifts and expansion that allow for favorable interactions with phosphorylated cannabinoid ligands.]]<br />
<br />
== Disease Relevance ==<br />
Because LPA<sub>1</sub> is expressed in so many tissues throughout the body, LPA<sub>1</sub> has been linked to the symptoms and progression of several different diseases and disorders.<ref name="number6">PMID: 20331961</ref><ref name="number7">PMID: 24367336</ref> For example, due to LPA<sub>1</sub>'s role in pain signaling, overexpression of this protein can cause both [https://en.wikipedia.org/wiki/Allodynia allodynia] or [https://en.wikipedia.org/wiki/Hyperalgesia hyperalgesia], common symptoms of multiple sclerosis or strokes.<ref name="number6">PMID: 20331961</ref> In addition, since LPA<sub>1</sub> helps in the myelination of Schwann cells, mutation of the receptor can also lead to a decrease in [https://en.wikipedia.org/wiki/Prepulse_inhibition prepulse inhibition], a general sign of schizophrenia.<ref name="number6">PMID: 20331961</ref> Lastly, because of the mitogen signaling activity of LPA<sub>1</sub>, abnormal expression or mutation of this receptor has been linked to tumor growth, survival, and migration in both liver and lung tumors.<ref name="number7">PMID: 24367336</ref> Part of this tumorigenesis can be explained by the action of <scene name='72/721543/His40/4'>His40</scene> on LPA<sub>1</sub> where, when protonated, increases LPA binding affinity by up to 1kcal/mol.<ref name="regpeps">PMID: 26091040</ref> Consequently, in the acidic environment produced by [https://en.wikipedia.org/wiki/Tumor_hypoxia hypoxic tumors] creating lactic acid, LPA<sub>1</sub> activity is increased, allowing these tumors to continue to proliferate, migrate, and survive.<ref name="number7">PMID: 24367336</ref> In contrast, the LPA<sub>1</sub> receptor also induces protective functions in different cardiovascular conditions. For example, in patients with heart disease, LPA<sub>1</sub> communicates with [[PI3K]], [https://en.wikipedia.org/wiki/Protein_kinase_B PKB], and [[ERK]] to create a hypertrophic response in the heart to offset reduced heart contractions.<ref name="number6">PMID: 20331961</ref><br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Chandler Mitchellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1172&diff=2587655Sandbox Reserved 11722016-04-18T22:03:30Z<p>Chandler Mitchell: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Central_Metabolism}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Lysophosphatidic Acid Receptor 1==<br />
<StructureSection load='4z34' size='340' side='right' caption='Cartoon representation of the LPA1 protein and its antagonist, ON7, colored in white. ([https://en.wikipedia.org/wiki/Protein_Data_Bank PDB] code [http://www.rcsb.org/pdb/explore/explore.do?structureId=4z34 4Z34]) ' scene='72/721543/Overallrainbow2/1'><br />
<br />
<br />
== Introduction ==<br />
Lysophosphatidic Acid Receptor 1 (commonly referred to as LPA<sub>1</sub>) is a [[G protein-coupled receptor]] and one of 6 different LPA receptors (LPA<sub>1</sub>-LPA<sub>6</sub>). These receptors bind the phospholipid derivative [https://en.wikipedia.org/wiki/Lysophosphatidic_acid lysophosphatidic acid (LPA)], a signaling molecule that acts as a potent [https://en.wikipedia.org/wiki/Mitogen mitogen] upon binding to one of its six receptors.<ref name="regpeps">PMID: 26091040</ref> LPA<sub>1</sub> is part of the larger [http://jb.oxfordjournals.org/content/131/6/767 EDG receptor family], which includes the more widely studied sphingosine 1-phopshate receptors.<ref name="regpeps">PMID: 26091040</ref> This receptor is responsible for initiating several different signaling cascades with different molecules and G-proteins.<ref name = 'Yung'>Yung, Y. C., N. C. Stoddard, and J. Chun. "LPA Receptor Signaling: Pharmacology, Physiology, and Pathophysiology." The Journal of Lipid Research 55.7 (2014): 1192-214. Web. 17 Feb. 2016.' </ref> These cascades ultimately result in growth, survival, and movement of cells, as well as neural cell development.<ref name = 'Chun'>Chun, J., Hla, T., Spiegel, S., and Moolenaar, W.H. “Lysophospholipid Receptors: Signaling and Biochemistry.” John Wiley & Sons, Inc. (2013) pp.i-xviii. 5 Feb. 2016.' </ref><br />
== Structure ==<br />
[[Image:Pic2proteo3.png|275 px|left|thumb|Figure 1: Surface representation of the LPA<sub>1</sub> receptor in tan interacting with its antagonist, ON7, shown in green and red sticks.The exterior of the protein was partially cut away to display the interior binding pocket.]]<br />
The LPA<sub>1</sub> receptor protein is composed of 364 amino acids with a molecular weight of approximately 41 kDa. Common to all G-protein coupled receptors, LPA<sub>1</sub> contains seven [http://kinemage.biochem.duke.edu/teaching/anatax/html/anatax.2a.html alpha helices] which make up the seven transmembrane spanning domains with three intracellular loops and three extracellular loops.<ref name = 'Hernández-Méndez'>Hernández-Méndez, Aurelio, Rocío Alcántara-Hernández, and J. Adolfo García-Sáinz. "Lysophosphatidic Acid LPA1-3 Receptors: Signaling, Regulation and in Silico Analysis of Their Putative Phosphorylation Sites." Receptors & Clinical Investigation Receptor Clin Invest 1.3 (2014). Web. 15 Feb. 2016.' </ref>. Within these helices is a binding pocket which stabilizes the binding of its ligand, LPA (Figure 1).<br />
=== Key Ligand Interactions ===<br />
[[Image:Amphbindingfinal.png|275 px|right|thumb|Figure 2: Electrostatic illustration of the amphipathic binding pocket of the LPA<sub>1</sub> receptor. This binding pocket was revealed by cutting away the exterior or the protein. This binding pocket, located in the interior of the protein, has both polar and nonpolar regions. The blue and red coloration highlight the positively and negatively charged regions, respectively, and the white color shows the nonpolar region of the binding pocket.]]<br />
The biological ligand of the LPA<sub>1</sub> receptor receptor is [https://en.wikipedia.org/wiki/Lysophosphatidic_acid lysophosphatidic acid (LPA)], a phospholipid that contains a long, nonpolar tail, a phosphate head, a chiral hydroxyl group, and an ester group. This receptor provides specificity for its ligand by the amphipathic binding pocket; the positive region on the left hand side of the pocket stabilizes the LPA's phosphate group, the nonpolar region at the bottom of the binding pocket stabilizes the hydrophobic tail of LPA, and the polar region at the top of the pocket stabilize binding of the ester and hydroxyl group (Figure 2). [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=8589 ONO-9780307 (ON7)] is an antagonist for LPA due to its large nonpolar region, chiral hydroxyl group, ester, and carboxylic acid which all resemble portions of the LPA molecule. Four separate interactions with this antagonist of LPA<sub>1</sub> help demonstrate the key interactions that stabilize the binding of the LPA phospholipid to this receptor. In the nonpolar region of the binding pocket, <scene name='72/721543/Nonpolar/2'>three non polar residues</scene> of LPA<sub>1</sub> stabilize the large nonpolar group of ON7. At the polar region, the ligand binding is stabilized by <scene name='72/721543/Arg124gln125/4'>Arg124 and Glu125</scene> forming ionic and polar interactions with the carboxylic acid and the hydroxyl group of ON7.<ref name="regpeps">PMID: 26091040</ref> In addition, interplay between <scene name='72/721543/Lys39_and_glu293/8'>Glu293 and Lys39</scene> causes another stabilizing component with the ON7 antagonist. Glu293 forms polar interactions with Lys39, positioning it in close proximity to to the carboxylic acid of ON7, which then interactions with Lys39 via ionic bonding.<ref name="regpeps">PMID: 26091040</ref> While Lys39 is highly conserved among all six LPA receptors, a neighboring histidine residue is specific to the LPA<sub>1</sub> receptor. <scene name='72/721543/His40/4'>His40</scene> forms both ionic and polar interactions with the carboxylic acid of ON7. Protonation of this residue greatly affects the binding affinity of LPA, leading to an increase in the pathways associated with cell proliferation and migration. Because cancerous tumors create acidic environments where His40 is protonated, this residue is an important link to tumor growth and cancer cell movement.<ref name="regpeps">PMID: 26091040</ref><br />
<br />
<br />
== Function ==<br />
The LPA<sub>1</sub> receptor is present in nearly all cells and tissues, and deletion of the LPA<sub>1</sub> receptor has physiological effects on every organ system, indicating its wide range of functions. Specifically, this receptor initiates downstream signaling cascades with three G<sub>α</sub> proteins: G<sub>i/o</sub>, G<sub>q/11</sub>, and G<sub>12/13</sub>. Specifically, G<sub>α</sub> proteins begin signaling cascades that activate [https://en.wikipedia.org/wiki/Phospholipase_C phospholipase C] and [[MAPK]]s that signal for cell proliferation, survival, and migration. <ref name = 'Yung'>Yung, Y. C., N. C. Stoddard, and J. Chun. "LPA Receptor Signaling: Pharmacology, Physiology, and Pathophysiology." The Journal of Lipid Research 55.7 (2014): 1192-214. Web. 17 Feb. 2016.' </ref>.Despite this receptor being expressed ubiquitously, LPA<sub>1</sub> is highly expressed in neural tissue, aiding in several different neurodevelopmental processes including growth and folding of the [https://www.dartmouth.edu/~rswenson/NeuroSci/chapter_11.html cerebral cortex] and the growth, survival, and migration of neural [https://en.wikipedia.org/wiki/Progenitor_cell progenitor cells].<ref name = 'Chun'>Chun, J., Hla, T., Spiegel, S., and Moolenaar, W.H. “Lysophospholipid Receptors: Signaling and Biochemistry.” John Wiley & Sons, Inc. (2013) pp.i-xviii. 5 Feb. 2016.' </ref> Finally, LPA<sub>1</sub> receptors expressed in neural tissue act through a signaling pathway with the [https://en.wikipedia.org/wiki/RAC1 Rac1] G-protein to aid in Schwann cell migration and myelination.<ref name="number5">PMID: 24115248</ref><br />
<br />
<br />
<br />
== Receptor Comparison ==<br />
<br />
=== Sphingosine 1-Phosphate Receptor ===<br />
LPA<sub>1</sub> belongs to the EDG (endothelial differentiation gene) family of [https://en.wikipedia.org/wiki/Lysophospholipid_receptor lysophospholipid receptors]. This family also includes the [https://en.wikipedia.org/wiki/S1PR1 sphingosine 1-phosphate receptor 1] (S1P<sub>1</sub>), which has many structural similarities to LPA<sub>1</sub>. In fact, the transmembrane regions share a sequence identity of 41%. <ref name = 'Chun, E.'>Chun, E., Thompson, A.A., Lui, W., Roth, C.B., Griffith, M.T., Katritch, V., Kunken, J., Xu, F., Cherezov, V., Hanson, M.A., and Stevens, R.C. “Fusion partner tool chest for the stabilization and crystallization of G protein-coupled receptors.” Structure 20, (2012) 967-976.' </ref> A defining difference between these two receptors is their mode of ligand access to the binding site. Where as the hydrophobic [https://en.wikipedia.org/wiki/Sphingosine-1-phosphate S1P ligand] enters S1P<sub>1</sub> via the membrane, LPA<sub>1</sub> has an extracellular opening that allows LPA access from the extracellular space <ref name="regpeps">PMID: 26091040</ref>. Structural evidence for this altered ligand pathway include global changes in the positioning of the extracellular loops (ECL) and transmembrane helices (TM). Specifically, this includes slight divergence of <scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene>, which is positioned 3 angstroms closer to TMVII compared to S1P<sub>1</sub>, and a repositioning of <scene name='72/721543/Ecl_regions/1'>ECL3</scene>, resulting in a divergence of 8 angstroms from S1P<sub>1</sub> <ref name="regpeps">PMID: 26091040</ref>. This narrowing of the gap between TMI and TMVII blocks membrane ligand access, while the greater distance between ECL3 and the other extracellular loops promotes extracellular access for LPA<sub>1</sub>. Additionally, ECL0 is helical in S1P<sub>1</sub>, but <scene name='72/721543/Ecl02ndstructure/1'>lacks secondary structure</scene> in LPA<sub>1</sub>. This increased flexibility that results further promotes favorable access from the extracellular space <ref name="regpeps">PMID: 26091040</ref>.<br />
<br />
<br />
[[Image:ECL3DistanceCM.png|200 px|left|thumb|Figure 1: Extracellular ligand access pathway on LPA<sub>1</sub>. Compared to S1P<sub>1</sub>, ECL3 shown in red is positioned 8 Å further from ECL0 and ECL2 shown in green. This largely contributes to the altered ligand binding pathway between LPA<sub>1</sub>, and S1P<sub>1</sub>]]<br />
<br />
=== Endocannabinoid Receptor 1 ===<br />
LPA<sub>1</sub> also is closely related to the first of the [http://www.nature.com/ijo/journal/v30/n1s/full/0803272a.html cannabinoid receptors]. This close relation gives CB<sub>1</sub> ([[Cannabinoid Receptor 1]]) the ability to bind to analogs of LPA and vice versa, which opens the possibility of metabolic crosstalk between the two signaling systems. This connection is made possible through ligand phosphorylation and dephosphorylation <ref name="regpeps">PMID: 26091040</ref>. Specifically, complementary access to the LPA<sub>1</sub> binding pocket can be achieved by phosphorylated CB<sub>1</sub> ligand analogs, while complementary access to the CB<sub>1</sub> binding site requires dephosphorylation of LPA<sub>1</sub> ligand analogs. In both cases, a ligand could serve as a primary [https://en.wikipedia.org/wiki/Selective_receptor_modulator receptor modulator] and a simultaneous [https://en.wikipedia.org/wiki/Prodrug prodrug] for a different receptor <ref name="regpeps">PMID: 26091040</ref>.<br />
<br />
<scene name='72/721543/Asp129_and_trp210/2'>Residues Asp129 and Trp210</scene> located within the hydrophobic binding pocket of LPA<sub>1</sub> may share responsibility for the preference for long unsaturated acyl chains. These residues are also interesting in regard to GPCR phylogenic evolution. <ref name="regpeps">PMID: 26091040</ref> Trp210 specifically only occurs in this position in 1% of all class A GPCR receptors and is unique to lysophospholipid and cannabinoid receptors. <ref name = 'Van Durme'>Van Durme, J., Horn, F., Costagliola, S., Vriend, G., and Vassart, G. “GRIS: glycoprotein-hormone receptor information system.” Mol. (2006) Endocrinol. 20, 2247-2255' </ref><br />
<br />
A model for lipid agonist binding generated through molecular modeling was used to dock two of the cannabinoid receptor CB<sub>1</sub>'s most abundant endogenous ligands into the LPA<sub>1</sub> binding pocket. <ref name="regpeps">PMID: 26091040</ref> Rotameric shifts of Trp210 and Trp271 leading to expansion of the binding pocket and the exposure of the π clouds of their indole rings provided favorable interactions with the double bonds of the phosphorylated cannabinoid ligands. This favorable binding provides evidence that the hydrophobic binding pockets of LPA<sub>1</sub> and CB<sub>1</sub> are able to favorably bind the same poly-unsaturated acyl chains with metabolically interconvertible head groups. <ref name="regpeps">PMID: 26091040</ref><br />
[[Image:TrpRotamericShiftsCM.png|200 px|left|thumb|Figure 1: Illustration of key LPA<sub>1</sub> binding pocket residues Trp210 and Trp271. These residues provide rotameric shifts and expansion that allow for favorable interactions with phosphorylated cannabinoid ligands.]]<br />
<br />
== Disease Relevance ==<br />
Because LPA<sub>1</sub> is expressed in so many tissues throughout the body, LPA<sub>1</sub> has been linked to the symptoms and progression of several different diseases and disorders.<ref name="number6">PMID: 20331961</ref><ref name="number7">PMID: 24367336</ref> For example, due to LPA<sub>1</sub>'s role in pain signaling, overexpression of this protein can cause both [https://en.wikipedia.org/wiki/Allodynia allodynia] or [https://en.wikipedia.org/wiki/Hyperalgesia hyperalgesia], common symptoms of multiple sclerosis or strokes.<ref name="number6">PMID: 20331961</ref> In addition, since LPA<sub>1</sub> helps in the myelination of Schwann cells, mutation of the receptor can also lead to a decrease in [https://en.wikipedia.org/wiki/Prepulse_inhibition prepulse inhibition], a general sign of schizophrenia.<ref name="number6">PMID: 20331961</ref> Lastly, because of the mitogen signaling activity of LPA<sub>1</sub>, abnormal expression or mutation of this receptor has been linked to tumor growth, survival, and migration in both liver and lung tumors.<ref name="number7">PMID: 24367336</ref> Part of this tumorigenesis can be explained by the action of <scene name='72/721543/His40/4'>His40</scene> on LPA<sub>1</sub> where, when protonated, increases LPA binding affinity by up to 1kcal/mol.<ref name="regpeps">PMID: 26091040</ref> Consequently, in the acidic environment produced by [https://en.wikipedia.org/wiki/Tumor_hypoxia hypoxic tumors] creating lactic acid, LPA<sub>1</sub> activity is increased, allowing these tumors to continue to proliferate, migrate, and survive.<ref name="number7">PMID: 24367336</ref> In contrast, the LPA<sub>1</sub> receptor also induces protective functions in different cardiovascular conditions. For example, in patients with heart disease, LPA<sub>1</sub> communicates with [[PI3K]], [https://en.wikipedia.org/wiki/Protein_kinase_B PKB], and [[ERK]] to create a hypertrophic response in the heart to offset reduced heart contractions.<ref name="number6">PMID: 20331961</ref><br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Chandler Mitchellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1172&diff=2587653Sandbox Reserved 11722016-04-18T21:54:47Z<p>Chandler Mitchell: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Central_Metabolism}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Lysophosphatidic Acid Receptor 1==<br />
<StructureSection load='4z34' size='340' side='right' caption='Cartoon representation of the LPA1 protein and its antagonist, ON7, colored in white. ([https://en.wikipedia.org/wiki/Protein_Data_Bank PDB] code [http://www.rcsb.org/pdb/explore/explore.do?structureId=4z34 4Z34]) ' scene='72/721543/Overallrainbow2/1'><br />
<br />
<br />
== Introduction ==<br />
Lysophosphatidic Acid Receptor 1 (commonly referred to as LPA<sub>1</sub>) is a [[G protein-coupled receptor]] and one of 6 different LPA receptors (LPA<sub>1</sub>-LPA<sub>6</sub>). These receptors bind the phospholipid derivative [https://en.wikipedia.org/wiki/Lysophosphatidic_acid lysophosphatidic acid (LPA)], a signaling molecule that acts as a potent [https://en.wikipedia.org/wiki/Mitogen mitogen] upon binding to one of its six receptors.<ref name="regpeps">PMID: 26091040</ref> LPA<sub>1</sub> is part of the larger [http://jb.oxfordjournals.org/content/131/6/767 EDG receptor family], which includes the more widely studied sphingosine 1-phopshate receptors.<ref name="regpeps">PMID: 26091040</ref> This receptor is responsible for initiating several different signaling cascades with different molecules and G-proteins.<ref name = 'Yung'>Yung, Y. C., N. C. Stoddard, and J. Chun. "LPA Receptor Signaling: Pharmacology, Physiology, and Pathophysiology." The Journal of Lipid Research 55.7 (2014): 1192-214. Web. 17 Feb. 2016.' </ref> These cascades ultimately result in growth, survival, and movement of cells, as well as neural cell development.<ref name = 'Chun'>Chun, J., Hla, T., Spiegel, S., and Moolenaar, W.H. “Lysophospholipid Receptors: Signaling and Biochemistry.” John Wiley & Sons, Inc. (2013) pp.i-xviii. 5 Feb. 2016.' </ref><br />
== Structure ==<br />
[[Image:Pic2proteo3.png|275 px|left|thumb|Figure 1: Surface representation of the LPA<sub>1</sub> receptor in tan interacting with its antagonist, ON7, shown in green and red sticks.The exterior of the protein was partially cut away to display the interior binding pocket.]]<br />
The LPA<sub>1</sub> receptor protein is composed of 364 amino acids with a molecular weight of approximately 41 kDa. Common to all G-protein coupled receptors, LPA<sub>1</sub> contains seven [http://kinemage.biochem.duke.edu/teaching/anatax/html/anatax.2a.html alpha helices] which make up the seven transmembrane spanning domains with three intracellular loops and three extracellular loops.<ref name = 'Hernández-Méndez'>Hernández-Méndez, Aurelio, Rocío Alcántara-Hernández, and J. Adolfo García-Sáinz. "Lysophosphatidic Acid LPA1-3 Receptors: Signaling, Regulation and in Silico Analysis of Their Putative Phosphorylation Sites." Receptors & Clinical Investigation Receptor Clin Invest 1.3 (2014). Web. 15 Feb. 2016.' </ref>. Within these helices is a binding pocket which stabilizes the binding of its ligand, LPA (Figure 1).<br />
=== Key Ligand Interactions ===<br />
[[Image:Amphbindingfinal.png|275 px|right|thumb|Figure 2: Electrostatic illustration of the amphipathic binding pocket of the LPA<sub>1</sub> receptor. This binding pocket was revealed by cutting away the exterior or the protein. This binding pocket, located in the interior of the protein, has both polar and nonpolar regions. The blue and red coloration highlight the positively and negatively charged regions, respectively, and the white color shows the nonpolar region of the binding pocket.]]<br />
The biological ligand of the LPA<sub>1</sub> receptor receptor is [https://en.wikipedia.org/wiki/Lysophosphatidic_acid lysophosphatidic acid (LPA)], a phospholipid that contains a long, nonpolar tail, a phosphate head, a chiral hydroxyl group, and an ester group. This receptor provides specificity for its ligand by the amphipathic binding pocket; the positive region on the left hand side of the pocket stabilizes the LPA's phosphate group, the nonpolar region at the bottom of the binding pocket stabilizes the hydrophobic tail of LPA, and the polar region at the top of the pocket stabilize binding of the ester and hydroxyl group (Figure 2). [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=8589 ONO-9780307 (ON7)] is an antagonist for LPA due to its large nonpolar region, chiral hydroxyl group, ester, and carboxylic acid which all resemble portions of the LPA molecule. Four separate interactions with this antagonist of LPA<sub>1</sub> help demonstrate the key interactions that stabilize the binding of the LPA phospholipid to this receptor. In the nonpolar region of the binding pocket, <scene name='72/721543/Nonpolar/2'>three non polar residues</scene> of LPA<sub>1</sub> stabilize the large nonpolar group of ON7. At the polar region, the ligand binding is stabilized by <scene name='72/721543/Arg124gln125/4'>Arg124 and Glu125</scene> forming ionic and polar interactions with the carboxylic acid and the hydroxyl group of ON7.<ref name="regpeps">PMID: 26091040</ref> In addition, interplay between <scene name='72/721543/Lys39_and_glu293/8'>Glu293 and Lys39</scene> causes another stabilizing component with the ON7 antagonist. Glu293 forms polar interactions with Lys39, positioning it in close proximity to to the carboxylic acid of ON7, which then interactions with Lys39 via ionic bonding.<ref name="regpeps">PMID: 26091040</ref> While Lys39 is highly conserved among all six LPA receptors, a neighboring histidine residue is specific to the LPA<sub>1</sub> receptor. <scene name='72/721543/His40/4'>His40</scene> forms both ionic and polar interactions with the carboxylic acid of ON7. Protonation of this residue greatly affects the binding affinity of LPA, leading to an increase in the pathways associated with cell proliferation and migration. Because cancerous tumors create acidic environments where His40 is protonated, this residue is an important link to tumor growth and cancer cell movement.<ref name="regpeps">PMID: 26091040</ref><br />
<br />
<br />
== Function ==<br />
The LPA<sub>1</sub> receptor is present in nearly all cells and tissues, and deletion of the LPA<sub>1</sub> receptor has physiological effects on every organ system, indicating its wide range of functions. Specifically, this receptor initiates downstream signaling cascades with three G<sub>α</sub> proteins: G<sub>i/o</sub>, G<sub>q/11</sub>, and G<sub>12/13</sub>. Specifically, G<sub>α</sub> proteins begin signaling cascades that activate [https://en.wikipedia.org/wiki/Phospholipase_C phospholipase C] and [[MAPK]]s that signal for cell proliferation, survival, and migration. <ref name = 'Yung'>Yung, Y. C., N. C. Stoddard, and J. Chun. "LPA Receptor Signaling: Pharmacology, Physiology, and Pathophysiology." The Journal of Lipid Research 55.7 (2014): 1192-214. Web. 17 Feb. 2016.' </ref>.Despite this receptor being expressed ubiquitously, LPA<sub>1</sub> is highly expressed in neural tissue, aiding in several different neurodevelopmental processes including growth and folding of the [https://www.dartmouth.edu/~rswenson/NeuroSci/chapter_11.html cerebral cortex] and the growth, survival, and migration of neural [https://en.wikipedia.org/wiki/Progenitor_cell progenitor cells].<ref name = 'Chun'>Chun, J., Hla, T., Spiegel, S., and Moolenaar, W.H. “Lysophospholipid Receptors: Signaling and Biochemistry.” John Wiley & Sons, Inc. (2013) pp.i-xviii. 5 Feb. 2016.' </ref> Finally, LPA<sub>1</sub> receptors expressed in neural tissue act through a signaling pathway with the [https://en.wikipedia.org/wiki/RAC1 Rac1] G-protein to aid in Schwann cell migration and myelination.<ref name="number5">PMID: 24115248</ref><br />
<br />
<br />
<br />
== Receptor Comparison ==<br />
<br />
=== Sphingosine 1-Phosphate Receptor ===<br />
LPA<sub>1</sub> belongs to the EDG (endothelial differentiation gene) family of [https://en.wikipedia.org/wiki/Lysophospholipid_receptor lysophospholipid receptors]. This family also includes the [https://en.wikipedia.org/wiki/S1PR1 sphingosine 1-phosphate receptor 1] (S1P<sub>1</sub>), which has many structural similarities to LPA<sub>1</sub>. In fact, the transmembrane regions share a sequence identity of 41%. <ref name = 'Chun, E.'>Chun, E., Thompson, A.A., Lui, W., Roth, C.B., Griffith, M.T., Katritch, V., Kunken, J., Xu, F., Cherezov, V., Hanson, M.A., and Stevens, R.C. “Fusion partner tool chest for the stabilization and crystallization of G protein-coupled receptors.” Structure 20, (2012) 967-976.' </ref> A defining difference between these two receptors is their mode of ligand access to the binding site. Where as the hydrophobic [https://en.wikipedia.org/wiki/Sphingosine-1-phosphate S1P ligand] enters S1P<sub>1</sub> via the membrane, LPA<sub>1</sub> has an extracellular opening that allows LPA access from the extracellular space <ref name="regpeps">PMID: 26091040</ref>. Structural evidence for this altered ligand pathway include global changes in the positioning of the extracellular loops (ECL) and transmembrane helices (TM). Specifically, this includes slight divergence of <scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene>, which is positioned 3 angstroms closer to TMVII compared to S1P<sub>1</sub>, and a repositioning of <scene name='72/721543/Ecl_regions/1'>ECL3</scene>, resulting in a divergence of 8 angstroms from S1P<sub>1</sub> <ref name="regpeps">PMID: 26091040</ref>. This narrowing of the gap between TMI and TMVII blocks membrane ligand access, while the greater distance between ECL3 and the other extracellular loops promotes extracellular access for LPA<sub>1</sub>. Additionally, ECL0 is helical in S1P<sub>1</sub>, but <scene name='72/721543/Ecl02ndstructure/1'>lacks secondary structure</scene> in LPA<sub>1</sub>. This increased flexibility that results further promotes favorable access from the extracellular space <ref name="regpeps">PMID: 26091040</ref>.<br />
<br />
<br />
[[Image:ECL3DistanceCM.png|200 px|left|thumb|Figure 1: Extracellular ligand access pathway on LPA<sub>1</sub>. Compared to S1P<sub>1</sub>, ECL3 shown in red is positioned 8 Å further from ECL0 and ECL2 shown in green. This largely contributes to the altered ligand binding pathway between LPA<sub>1</sub>, and S1P<sub>1</sub>]]<br />
<br />
=== Endocannabinoid Receptor 1 ===<br />
LPA<sub>1</sub> also is closely related to the first of the [http://www.nature.com/ijo/journal/v30/n1s/full/0803272a.html cannabinoid receptors]. This close relation gives CB<sub>1</sub> ([[Cannabinoid Receptor 1]]) the ability to bind to analogs of LPA and vice versa, which opens the possibility of metabolic crosstalk between the two signaling systems. This connection is made possible through ligand phosphorylation and dephosphorylation <ref name="regpeps">PMID: 26091040</ref>. Specifically, complementary access to the LPA<sub>1</sub> binding pocket can be achieved by phosphorylated CB<sub>1</sub> ligand analogs, while complementary access to the CB<sub>1</sub> binding site requires dephosphorylation of LPA<sub>1</sub> ligand analogs. In both cases, a ligand could serve as a primary [https://en.wikipedia.org/wiki/Selective_receptor_modulator receptor modulator] and a simultaneous [https://en.wikipedia.org/wiki/Prodrug prodrug] for a different receptor <ref name="regpeps">PMID: 26091040</ref>.<br />
<br />
<scene name='72/721543/Asp129_and_trp210/2'>Residues Asp129 and Trp210</scene> located within the hydrophobic binding pocket of LPA<sub>1</sub> may share responsibility for the preference for long unsaturated acyl chains. These residues are also interesting in regard to GPCR phylogenic evolution. <ref name="regpeps">PMID: 26091040</ref> Trp210 specifically only occurs in this position in 1% of all class A GPCR receptors and is unique to lysophospholipid and cannabinoid receptors. <ref name = 'Van Durme'>Van Durme, J., Horn, F., Costagliola, S., Vriend, G., and Vassart, G. “GRIS: glycoprotein-hormone receptor information system.” Mol. (2006) Endocrinol. 20, 2247-2255' </ref><br />
<br />
A model for lipid agonist binding generated through molecular modeling was used to dock two of the cannabinoid receptor CB<sub>1</sub>'s most abundant endogenous ligands into the LPA<sub>1</sub> binding pocket. <ref name="regpeps">PMID: 26091040</ref> Rotameric shifts of Trp210 and Trp271 leading to expansion of the binding pocket and the exposure of the π clouds of their indole rings provided favorable interactions with the double bonds of the phosphorylated cannabinoid ligands. This favorable binding provides evidence that the hydrophobic binding pockets of LPA<sub>1</sub> and CB<sub>1</sub> are able to favorably bind the same poly-unsaturated acyl chains with metabolically interconvertible head groups. <ref name="regpeps">PMID: 26091040</ref><br />
[[Image:TrpRotamericShiftsCM.png|200 px|left|thumb|Figure 1: Electrostatic illustration of the amphipathic binding pocket of the LPA<sub>1</sub> receptor. This binding pocket, located in the interior of the protein, has both polar and nonpolar regions. The blue and red coloration highlight the positively and negatively charged regions, respectively, and the white color shows the nonpolar region of the binding pocket.]]<br />
<br />
== Disease Relevance ==<br />
Because LPA<sub>1</sub> is expressed in so many tissues throughout the body, LPA<sub>1</sub> has been linked to the symptoms and progression of several different diseases and disorders.<ref name="number6">PMID: 20331961</ref><ref name="number7">PMID: 24367336</ref> For example, due to LPA<sub>1</sub>'s role in pain signaling, overexpression of this protein can cause both [https://en.wikipedia.org/wiki/Allodynia allodynia] or [https://en.wikipedia.org/wiki/Hyperalgesia hyperalgesia], common symptoms of multiple sclerosis or strokes.<ref name="number6">PMID: 20331961</ref> In addition, since LPA<sub>1</sub> helps in the myelination of Schwann cells, mutation of the receptor can also lead to a decrease in [https://en.wikipedia.org/wiki/Prepulse_inhibition prepulse inhibition], a general sign of schizophrenia.<ref name="number6">PMID: 20331961</ref> Lastly, because of the mitogen signaling activity of LPA<sub>1</sub>, abnormal expression or mutation of this receptor has been linked to tumor growth, survival, and migration in both liver and lung tumors.<ref name="number7">PMID: 24367336</ref> Part of this tumorigenesis can be explained by the action of <scene name='72/721543/His40/4'>His40</scene> on LPA<sub>1</sub> where, when protonated, increases LPA binding affinity by up to 1kcal/mol.<ref name="regpeps">PMID: 26091040</ref> Consequently, in the acidic environment produced by [https://en.wikipedia.org/wiki/Tumor_hypoxia hypoxic tumors] creating lactic acid, LPA<sub>1</sub> activity is increased, allowing these tumors to continue to proliferate, migrate, and survive.<ref name="number7">PMID: 24367336</ref> In contrast, the LPA<sub>1</sub> receptor also induces protective functions in different cardiovascular conditions. For example, in patients with heart disease, LPA<sub>1</sub> communicates with [[PI3K]], [https://en.wikipedia.org/wiki/Protein_kinase_B PKB], and [[ERK]] to create a hypertrophic response in the heart to offset reduced heart contractions.<ref name="number6">PMID: 20331961</ref><br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Chandler Mitchellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1172&diff=2586784Sandbox Reserved 11722016-04-12T13:50:53Z<p>Chandler Mitchell: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Central_Metabolism}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Lysophosphatidic Acid Receptor 1==<br />
<StructureSection load='4z34' size='340' side='right' caption='Cartoon representation of the LPA1 protein and its antagonist, ON7, colored in white. ([https://en.wikipedia.org/wiki/Protein_Data_Bank PDB] code [http://www.rcsb.org/pdb/explore/explore.do?structureId=4z34 4Z34]) ' scene='72/721543/Overallrainbow2/1'><br />
<br />
<br />
== Introduction ==<br />
Lysophosphatidic Acid Receptor 1 (commonly referred to as LPA<sub>1</sub>) is a [[G protein-coupled receptor]] and one of 6 different LPA receptors (LPA<sub>1</sub>-LPA<sub>6</sub>) that binds the phospholipid derivative [https://en.wikipedia.org/wiki/Lysophosphatidic_acid lysophosphatidic acid (LPA)], a signaling molecule that acts as a potent [https://en.wikipedia.org/wiki/Mitogen mitogen] upon binding to one of its six receptors.<ref name="regpeps">PMID: 26091040</ref> LPA<sub>1</sub> is part of the larger [http://jb.oxfordjournals.org/content/131/6/767 EDG receptor family] which includes the more widely known sphingosine 1-phopshate receptors.<br />
== Structure ==<br />
[[Image:Amphbindingfinal.png|200 px|left|thumb|Figure 1: Electrostatic illustration of the amphipathic binding pocket of the LPA<sub>1</sub> receptor. This binding pocket, located in the interior of the protein, has both polar and nonpolar regions. The blue and red coloration highlight the positively and negatively charged regions, respectively, and the white color shows the nonpolar region of the binding pocket.]]<br />
The LPA<sub>1</sub> receptor protein is composed of 364 amino acids with a mass of approximately 41 kDa. Just as other G-protein coupled receptors, LPA<sub>1</sub> contains seven [http://kinemage.biochem.duke.edu/teaching/anatax/html/anatax.2a.html alpha helices] which make up the seven transmembrane spanning domains with three intracellular loops and three extracellular loops. The amino terminus of this protein is located on the extracellular side of the membrane, while the carboxyl terminus is located on the intracellular side of the membrane.<ref name = 'Hernández-Méndez'>Hernández-Méndez, Aurelio, Rocío Alcántara-Hernández, and J. Adolfo García-Sáinz. "Lysophosphatidic Acid LPA1-3 Receptors: Signaling, Regulation and in Silico Analysis of Their Putative Phosphorylation Sites." Receptors & Clinical Investigation Receptor Clin Invest 1.3 (2014). Web. 15 Feb. 2016.' </ref>. Within these helices is an amphipathic binding pocket which stabilizes the binding of its ligand, LPA.<br />
=== Key Ligand Interactions ===<br />
[[Image:Ligandpocket2.png|200 px|right|thumb|Figure 2: Surface representation of the LPA<sub>1</sub> receptor in tan interacting with its antagonist, ON7, shown in green and red sticks.]]<br />
Three separate interactions with an antagonist of LPA<sub>1</sub>, ON7, help demonstrate the key interactions that stabilize the binding of the LPA phospholipid to this receptor. At the polar region of the binding pocket, the majority of this region is stabilized by <scene name='72/721543/Arg124gln125/3'>Arg124 and Gln125</scene> forming ionic and polar interactions with the carboxylic acid and the hydroxyl group of ON7.<ref name="regpeps">PMID: 26091040</ref> In addition, interplay between <scene name='72/721543/Lys39_and_glu293/7'>Glu293 and Lys39</scene> causes another stabilizing component of the ON7 antagonist. Glu293 forms polar interactions with Lys39, positioning it in close proximity to to the carboxylic acid of ON7, which then interactions with Lys39 via ionic bonding.<ref name="regpeps">PMID: 26091040</ref> While Lys39 is highly conserved among all six LPA receptors, a His40 residue is present that is specific to the LPA<sub>1</sub> receptor. <scene name='72/721543/His40/1'>His40</scene> forms both ionic and polar interactions with the carboxylic acid of ON7. The protonation of this residue has been found to greatly affect the binding affinity of LPA, and is an important link to tumor growth and survival in acidic environments.<ref name="regpeps">PMID: 26091040</ref><br />
<br />
<br />
== Function ==<br />
The LPA<sub>1</sub> receptor is present in nearly all cells and tissues throughout the body, and deletion of the LPA<sub>1</sub> receptor has been found to have physiological effects on every organ system, indicating its wide range of functions. Specifically, this receptor has been found to initiate downstream signaling cascades with three G<sub>α</sub> proteins: G<sub>i/o</sub>, G<sub>q/11</sub>, and G<sub>12/13</sub>. These G<sub>α</sub> proteins begin signaling cascades with molecules such as [https://en.wikipedia.org/wiki/Phospholipase_C phospholipase C] and [[MAPK]] that signal for cell proliferation, survival, and migration. <ref name = 'Yung'>Yung, Y. C., N. C. Stoddard, and J. Chun. "LPA Receptor Signaling: Pharmacology, Physiology, and Pathophysiology." The Journal of Lipid Research 55.7 (2014): 1192-214. Web. 17 Feb. 2016.' </ref>.Despite this receptor being expressed throughout the body, LPA<sub>1</sub> has been found to be expressed highly in neural tissue, aiding in several different neurodevelopmental processes including growth and folding of the [https://www.dartmouth.edu/~rswenson/NeuroSci/chapter_11.html cerebral cortex] and the growth, survival, and migration of neural [https://en.wikipedia.org/wiki/Progenitor_cell progenitor cells] through its different [https://en.wikipedia.org/wiki/G_protein G-protein] regulated pathways.<ref name = 'Chun'>Chun, J., Hla, T., Spiegel, S., and Moolenaar, W.H. “Lysophospholipid Receptors: Signaling and Biochemistry.” John Wiley & Sons, Inc. (2013) pp.i-xviii. 5 Feb. 2016.' </ref>. Finally, LPA1 receptors expressed in neural tissue aid in Schwann cell migration and myelination through a signaling pathway with the [https://en.wikipedia.org/wiki/RAC1 Rac1] G-protein.<ref name="number5">PMID: 24115248</ref>.<br />
<br />
<br />
<br />
== Receptor Comparison ==<br />
<br />
=== Sphingosine 1-Phosphate Receptor ===<br />
LPA<sub>1</sub> belongs to the EDG (endothelial differentiation gene) family of [https://en.wikipedia.org/wiki/Lysophospholipid_receptor lysophospholipid receptors]. This family also includes the [https://en.wikipedia.org/wiki/S1PR1 sphingosine 1-phosphate receptor 1] (S1P<sub>1</sub>), which has many structural similarities to LPA<sub>1</sub>. In fact, the transmembrane regions share a sequence identity of 41%. <ref name = 'Chun, E.'>Chun, E., Thompson, A.A., Lui, W., Roth, C.B., Griffith, M.T., Katritch, V., Kunken, J., Xu, F., Cherezov, V., Hanson, M.A., and Stevens, R.C. “Fusion partner tool chest for the stabilization and crystallization of G protein-coupled receptors.” Structure 20, (2012) 967-976.' </ref> A defining difference between these two receptors is their mode of ligand access to the binding site. Where as the hydrophobic [https://en.wikipedia.org/wiki/Sphingosine-1-phosphate S1P ligand] enters S1P<sub>1</sub> via the membrane, LPA<sub>1</sub> has an extracellular opening that allows LPA access from the extracellular space <ref name="regpeps">PMID: 26091040</ref>. Structural evidence for this altered ligand pathway include global changes in the positioning of the extracellular loops (ECL) and transmembrane helices (TM). Specifically, this includes slight divergence of <scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene>, which is positioned 3 angstroms closer to TMVII compared to S1P<sub>1</sub>, and a repositioning of <scene name='72/721543/Ecl_regions/1'>ECL3</scene>, resulting in a divergence of 8 angstroms from S1P<sub>1</sub> <ref name="regpeps">PMID: 26091040</ref>. This narrowing of the gap between TMI and TMVII blocks membrane ligand access, while the greater distance between ECL3 and the other extracellular loops promotes extracellular access for LPA<sub>1</sub>. Additionally, ECL0 is helical in S1P<sub>1</sub>, but <scene name='72/721543/Ecl02ndstructure/1'>lacks secondary structure</scene> in LPA<sub>1</sub>. This increased flexibility that results further promotes favorable access from the extracellular space <ref name="regpeps">PMID: 26091040</ref>.<br />
<br />
<br />
[[Image:ECL3DistanceCM.png|200 px|left|thumb|Figure 1: Electrostatic illustration of the amphipathic binding pocket of the LPA<sub>1</sub> receptor. This binding pocket, located in the interior of the protein, has both polar and nonpolar regions. The blue and red coloration highlight the positively and negatively charged regions, respectively, and the white color shows the nonpolar region of the binding pocket.]]<br />
<br />
=== Endocannabinoid Receptor 1 ===<br />
LPA<sub>1</sub> also is closely related to the first of the [http://www.nature.com/ijo/journal/v30/n1s/full/0803272a.html cannabinoid receptors]. This close relation gives CB<sub>1</sub> ([[Cannabinoid Receptor 1]]) the ability to bind to analogs of LPA and vice versa, which opens the possibility of metabolic crosstalk between the two signaling systems. This connection is made possible through ligand phosphorylation and dephosphorylation <ref name="regpeps">PMID: 26091040</ref>. Specifically, complementary access to the LPA<sub>1</sub> binding pocket can be achieved by phosphorylated CB<sub>1</sub> ligand analogs, while complementary access to the CB<sub>1</sub> binding site requires dephosphorylation of LPA<sub>1</sub> ligand analogs. In both cases, a ligand could serve as a primary [https://en.wikipedia.org/wiki/Selective_receptor_modulator receptor modulator] and a simultaneous [https://en.wikipedia.org/wiki/Prodrug prodrug] for a different receptor <ref name="regpeps">PMID: 26091040</ref>.<br />
<br />
<scene name='72/721543/Asp129_and_trp210/2'>Residues Asp129 and Trp210</scene> located within the hydrophobic binding pocket of LPA<sub>1</sub> may share responsibility for the preference for long unsaturated acyl chains. These residues are also interesting in regard to GPCR phylogenic evolution. <ref name="regpeps">PMID: 26091040</ref> Trp210 specifically only occurs in this position in 1% of all class A GPCR receptors and is unique to lysophospholipid and cannabinoid receptors. <ref name = 'Van Durme'>Van Durme, J., Horn, F., Costagliola, S., Vriend, G., and Vassart, G. “GRIS: glycoprotein-hormone receptor information system.” Mol. (2006) Endocrinol. 20, 2247-2255' </ref><br />
<br />
A model for lipid agonist binding generated through molecular modeling was used to dock two of the cannabinoid receptor CB<sub>1</sub>'s most abundant endogenous ligands into the LPA<sub>1</sub> binding pocket. <ref name="regpeps">PMID: 26091040</ref> Rotameric shifts of Trp210 and Trp271 leading to expansion of the binding pocket and the exposure of the π clouds of their indole rings provided favorable interactions with the double bonds of the phosphorylated cannabinoid ligands. This favorable binding provides evidence that the hydrophobic binding pockets of LPA<sub>1</sub> and CB<sub>1</sub> are able to favorably bind the same poly-unsaturated acyl chains with metabolically interconvertible head groups. <ref name="regpeps">PMID: 26091040</ref><br />
[[Image:TrpRotamericShiftsCM.png|200 px|left|thumb|Figure 1: Electrostatic illustration of the amphipathic binding pocket of the LPA<sub>1</sub> receptor. This binding pocket, located in the interior of the protein, has both polar and nonpolar regions. The blue and red coloration highlight the positively and negatively charged regions, respectively, and the white color shows the nonpolar region of the binding pocket.]]<br />
<br />
== Disease Relevance ==<br />
Because LPA<sub>1</sub> is expressed in so many tissues throughout the body, it has been linked to the symptoms and progression of several different diseases and disorders. For example, due to LPA<sub>1</sub>'s role in pain signaling, overexpression of this protein can cause both [https://en.wikipedia.org/wiki/Allodynia allodynia] or [https://en.wikipedia.org/wiki/Hyperalgesia hyperalgesia], common symptoms of multiple sclerosis or strokes. In addition, since LPA<sub>1</sub> helps in the myelination of Schwann cells, mutation of the receptor can also lead to a decrease in [https://en.wikipedia.org/wiki/Prepulse_inhibition prepulse inhibition], a general sign of schizophrenia.<ref name="number6">PMID: 20331961</ref>.Lastly, because of the mitogen signaling activity of LPA<sub>1</sub>, abnormal expression or mutation of this receptor has been linked to tumor growth, survival, and migration in both liver and lung tumors. As recently discussed, the His40 on LPA<sub>1</sub>, when protonated, increased LPA binding affinity is increase by up to 1kcal/mol. Because of this, in an acidic environment that is typically produced by [https://en.wikipedia.org/wiki/Tumor_hypoxia hypoxic tumors] creating lactic acid, LPA<sub>1</sub> activity is increased, allowing these tumors to continue to proliferate, migrate, and survive.<ref name="number7">PMID: 24367336</ref>. In contrast, the LPA<sub>1</sub> receptor has also been found to induce protective functions in the presence of a particular illness. For example, in patients with heart disease, LPA<sub>1</sub> has been found to communicate with [[PI3K]], [https://en.wikipedia.org/wiki/Protein_kinase_B PKB], and [[ERK]] to create a hypertrophic response in the heart in order to offset reduced heart contractions.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Chandler Mitchellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1172&diff=2586782Sandbox Reserved 11722016-04-12T13:50:15Z<p>Chandler Mitchell: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Central_Metabolism}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Lysophosphatidic Acid Receptor 1==<br />
<StructureSection load='4z34' size='340' side='right' caption='Cartoon representation of the LPA1 protein and its antagonist, ON7, colored in white. ([https://en.wikipedia.org/wiki/Protein_Data_Bank PDB] code [http://www.rcsb.org/pdb/explore/explore.do?structureId=4z34 4Z34]) ' scene='72/721543/Overallrainbow2/1'><br />
<br />
<br />
== Introduction ==<br />
Lysophosphatidic Acid Receptor 1 (commonly referred to as LPA<sub>1</sub>) is a [[G protein-coupled receptor]] and one of 6 different LPA receptors (LPA<sub>1</sub>-LPA<sub>6</sub>) that binds the phospholipid derivative [https://en.wikipedia.org/wiki/Lysophosphatidic_acid lysophosphatidic acid (LPA)], a signaling molecule that acts as a potent [https://en.wikipedia.org/wiki/Mitogen mitogen] upon binding to one of its six receptors.<ref name="regpeps">PMID: 26091040</ref> LPA<sub>1</sub> is part of the larger [http://jb.oxfordjournals.org/content/131/6/767 EDG receptor family] which includes the more widely known sphingosine 1-phopshate receptors.<br />
== Structure ==<br />
[[Image:Amphbindingfinal.png|200 px|left|thumb|Figure 1: Electrostatic illustration of the amphipathic binding pocket of the LPA<sub>1</sub> receptor. This binding pocket, located in the interior of the protein, has both polar and nonpolar regions. The blue and red coloration highlight the positively and negatively charged regions, respectively, and the white color shows the nonpolar region of the binding pocket.]]<br />
The LPA<sub>1</sub> receptor protein is composed of 364 amino acids with a mass of approximately 41 kDa. Just as other G-protein coupled receptors, LPA<sub>1</sub> contains seven [http://kinemage.biochem.duke.edu/teaching/anatax/html/anatax.2a.html alpha helices] which make up the seven transmembrane spanning domains with three intracellular loops and three extracellular loops. The amino terminus of this protein is located on the extracellular side of the membrane, while the carboxyl terminus is located on the intracellular side of the membrane.<ref name = 'Hernández-Méndez'>Hernández-Méndez, Aurelio, Rocío Alcántara-Hernández, and J. Adolfo García-Sáinz. "Lysophosphatidic Acid LPA1-3 Receptors: Signaling, Regulation and in Silico Analysis of Their Putative Phosphorylation Sites." Receptors & Clinical Investigation Receptor Clin Invest 1.3 (2014). Web. 15 Feb. 2016.' </ref>. Within these helices is an amphipathic binding pocket which stabilizes the binding of its ligand, LPA.<br />
=== Key Ligand Interactions ===<br />
[[Image:Ligandpocket2.png|200 px|right|thumb|Figure 2: Surface representation of the LPA<sub>1</sub> receptor in tan interacting with its antagonist, ON7, shown in green and red sticks.]]<br />
Three separate interactions with an antagonist of LPA<sub>1</sub>, ON7, help demonstrate the key interactions that stabilize the binding of the LPA phospholipid to this receptor. At the polar region of the binding pocket, the majority of this region is stabilized by <scene name='72/721543/Arg124gln125/3'>Arg124 and Gln125</scene> forming ionic and polar interactions with the carboxylic acid and the hydroxyl group of ON7.<ref name="regpeps">PMID: 26091040</ref> In addition, interplay between <scene name='72/721543/Lys39_and_glu293/7'>Glu293 and Lys39</scene> causes another stabilizing component of the ON7 antagonist. Glu293 forms polar interactions with Lys39, positioning it in close proximity to to the carboxylic acid of ON7, which then interactions with Lys39 via ionic bonding.<ref name="regpeps">PMID: 26091040</ref> While Lys39 is highly conserved among all six LPA receptors, a His40 residue is present that is specific to the LPA<sub>1</sub> receptor. <scene name='72/721543/His40/1'>His40</scene> forms both ionic and polar interactions with the carboxylic acid of ON7. The protonation of this residue has been found to greatly affect the binding affinity of LPA, and is an important link to tumor growth and survival in acidic environments.<ref name="regpeps">PMID: 26091040</ref><br />
<br />
<br />
== Function ==<br />
The LPA<sub>1</sub> receptor is present in nearly all cells and tissues throughout the body, and deletion of the LPA<sub>1</sub> receptor has been found to have physiological effects on every organ system, indicating its wide range of functions. Specifically, this receptor has been found to initiate downstream signaling cascades with three G<sub>α</sub> proteins: G<sub>i/o</sub>, G<sub>q/11</sub>, and G<sub>12/13</sub>. These G<sub>α</sub> proteins begin signaling cascades with molecules such as [https://en.wikipedia.org/wiki/Phospholipase_C phospholipase C] and [[MAPK]] that signal for cell proliferation, survival, and migration. <ref name = 'Yung'>Yung, Y. C., N. C. Stoddard, and J. Chun. "LPA Receptor Signaling: Pharmacology, Physiology, and Pathophysiology." The Journal of Lipid Research 55.7 (2014): 1192-214. Web. 17 Feb. 2016.' </ref>.Despite this receptor being expressed throughout the body, LPA<sub>1</sub> has been found to be expressed highly in neural tissue, aiding in several different neurodevelopmental processes including growth and folding of the [https://www.dartmouth.edu/~rswenson/NeuroSci/chapter_11.html cerebral cortex] and the growth, survival, and migration of neural [https://en.wikipedia.org/wiki/Progenitor_cell progenitor cells] through its different [https://en.wikipedia.org/wiki/G_protein G-protein] regulated pathways.<ref name = 'Chun'>Chun, J., Hla, T., Spiegel, S., and Moolenaar, W.H. “Lysophospholipid Receptors: Signaling and Biochemistry.” John Wiley & Sons, Inc. (2013) pp.i-xviii. 5 Feb. 2016.' </ref>. Finally, LPA1 receptors expressed in neural tissue aid in Schwann cell migration and myelination through a signaling pathway with the [https://en.wikipedia.org/wiki/RAC1 Rac1] G-protein.<ref name="number5">PMID: 24115248</ref>.<br />
<br />
<br />
<br />
== Receptor Comparison ==<br />
<br />
=== Sphingosine 1-Phosphate Receptor ===<br />
LPA<sub>1</sub> belongs to the EDG (endothelial differentiation gene) family of [https://en.wikipedia.org/wiki/Lysophospholipid_receptor lysophospholipid receptors]. This family also includes the [https://en.wikipedia.org/wiki/S1PR1 sphingosine 1-phosphate receptor 1] (S1P<sub>1</sub>), which has many structural similarities to LPA<sub>1</sub>. In fact, the transmembrane regions share a sequence identity of 41%. <ref name = 'Chun, E.'>Chun, E., Thompson, A.A., Lui, W., Roth, C.B., Griffith, M.T., Katritch, V., Kunken, J., Xu, F., Cherezov, V., Hanson, M.A., and Stevens, R.C. “Fusion partner tool chest for the stabilization and crystallization of G protein-coupled receptors.” Structure 20, (2012) 967-976.' </ref> A defining difference between these two receptors is their mode of ligand access to the binding site. Where as the hydrophobic [https://en.wikipedia.org/wiki/Sphingosine-1-phosphate S1P ligand] enters S1P<sub>1</sub> via the membrane, LPA<sub>1</sub> has an extracellular opening that allows LPA access from the extracellular space <ref name="regpeps">PMID: 26091040</ref>. Structural evidence for this altered ligand pathway include global changes in the positioning of the extracellular loops (ECL) and transmembrane helices (TM). Specifically, this includes slight divergence of <scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene>, which is positioned 3 angstroms closer to TMVII compared to S1P<sub>1</sub>, and a repositioning of <scene name='72/721543/Ecl_regions/1'>ECL3</scene>, resulting in a divergence of 8 angstroms from S1P<sub>1</sub> <ref name="regpeps">PMID: 26091040</ref>. This narrowing of the gap between TMI and TMVII blocks membrane ligand access, while the greater distance between ECL3 and the other extracellular loops promotes extracellular access for LPA<sub>1</sub>. Additionally, ECL0 is helical in S1P<sub>1</sub>, but <scene name='72/721543/Ecl02ndstructure/1'>lacks secondary structure</scene> in LPA<sub>1</sub>. This increased flexibility that results further promotes favorable access from the extracellular space <ref name="regpeps">PMID: 26091040</ref>.<br />
<br />
<scene name='72/721543/Ecl02ndstructure/1'>TextToBeDisplayed</scene><br />
<br />
[[Image:ECL3DistanceCM.png|200 px|left|thumb|Figure 1: Electrostatic illustration of the amphipathic binding pocket of the LPA<sub>1</sub> receptor. This binding pocket, located in the interior of the protein, has both polar and nonpolar regions. The blue and red coloration highlight the positively and negatively charged regions, respectively, and the white color shows the nonpolar region of the binding pocket.]]<br />
<br />
=== Endocannabinoid Receptor 1 ===<br />
LPA<sub>1</sub> also is closely related to the first of the [http://www.nature.com/ijo/journal/v30/n1s/full/0803272a.html cannabinoid receptors]. This close relation gives CB<sub>1</sub> ([[Cannabinoid Receptor 1]]) the ability to bind to analogs of LPA and vice versa, which opens the possibility of metabolic crosstalk between the two signaling systems. This connection is made possible through ligand phosphorylation and dephosphorylation <ref name="regpeps">PMID: 26091040</ref>. Specifically, complementary access to the LPA<sub>1</sub> binding pocket can be achieved by phosphorylated CB<sub>1</sub> ligand analogs, while complementary access to the CB<sub>1</sub> binding site requires dephosphorylation of LPA<sub>1</sub> ligand analogs. In both cases, a ligand could serve as a primary [https://en.wikipedia.org/wiki/Selective_receptor_modulator receptor modulator] and a simultaneous [https://en.wikipedia.org/wiki/Prodrug prodrug] for a different receptor <ref name="regpeps">PMID: 26091040</ref>.<br />
<br />
<scene name='72/721543/Asp129_and_trp210/2'>Residues Asp129 and Trp210</scene> located within the hydrophobic binding pocket of LPA<sub>1</sub> may share responsibility for the preference for long unsaturated acyl chains. These residues are also interesting in regard to GPCR phylogenic evolution. <ref name="regpeps">PMID: 26091040</ref> Trp210 specifically only occurs in this position in 1% of all class A GPCR receptors and is unique to lysophospholipid and cannabinoid receptors. <ref name = 'Van Durme'>Van Durme, J., Horn, F., Costagliola, S., Vriend, G., and Vassart, G. “GRIS: glycoprotein-hormone receptor information system.” Mol. (2006) Endocrinol. 20, 2247-2255' </ref><br />
<br />
A model for lipid agonist binding generated through molecular modeling was used to dock two of the cannabinoid receptor CB<sub>1</sub>'s most abundant endogenous ligands into the LPA<sub>1</sub> binding pocket. <ref name="regpeps">PMID: 26091040</ref> Rotameric shifts of Trp210 and Trp271 leading to expansion of the binding pocket and the exposure of the π clouds of their indole rings provided favorable interactions with the double bonds of the phosphorylated cannabinoid ligands. This favorable binding provides evidence that the hydrophobic binding pockets of LPA<sub>1</sub> and CB<sub>1</sub> are able to favorably bind the same poly-unsaturated acyl chains with metabolically interconvertible head groups. <ref name="regpeps">PMID: 26091040</ref><br />
[[Image:TrpRotamericShiftsCM.png|200 px|left|thumb|Figure 1: Electrostatic illustration of the amphipathic binding pocket of the LPA<sub>1</sub> receptor. This binding pocket, located in the interior of the protein, has both polar and nonpolar regions. The blue and red coloration highlight the positively and negatively charged regions, respectively, and the white color shows the nonpolar region of the binding pocket.]]<br />
<br />
== Disease Relevance ==<br />
Because LPA<sub>1</sub> is expressed in so many tissues throughout the body, it has been linked to the symptoms and progression of several different diseases and disorders. For example, due to LPA<sub>1</sub>'s role in pain signaling, overexpression of this protein can cause both [https://en.wikipedia.org/wiki/Allodynia allodynia] or [https://en.wikipedia.org/wiki/Hyperalgesia hyperalgesia], common symptoms of multiple sclerosis or strokes. In addition, since LPA<sub>1</sub> helps in the myelination of Schwann cells, mutation of the receptor can also lead to a decrease in [https://en.wikipedia.org/wiki/Prepulse_inhibition prepulse inhibition], a general sign of schizophrenia.<ref name="number6">PMID: 20331961</ref>.Lastly, because of the mitogen signaling activity of LPA<sub>1</sub>, abnormal expression or mutation of this receptor has been linked to tumor growth, survival, and migration in both liver and lung tumors. As recently discussed, the His40 on LPA<sub>1</sub>, when protonated, increased LPA binding affinity is increase by up to 1kcal/mol. Because of this, in an acidic environment that is typically produced by [https://en.wikipedia.org/wiki/Tumor_hypoxia hypoxic tumors] creating lactic acid, LPA<sub>1</sub> activity is increased, allowing these tumors to continue to proliferate, migrate, and survive.<ref name="number7">PMID: 24367336</ref>. In contrast, the LPA<sub>1</sub> receptor has also been found to induce protective functions in the presence of a particular illness. For example, in patients with heart disease, LPA<sub>1</sub> has been found to communicate with [[PI3K]], [https://en.wikipedia.org/wiki/Protein_kinase_B PKB], and [[ERK]] to create a hypertrophic response in the heart in order to offset reduced heart contractions.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Chandler Mitchellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1172&diff=2586781Sandbox Reserved 11722016-04-12T13:46:34Z<p>Chandler Mitchell: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Central_Metabolism}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Lysophosphatidic Acid Receptor 1==<br />
<StructureSection load='4z34' size='340' side='right' caption='Cartoon representation of the LPA1 protein and its antagonist, ON7, colored in white. ([https://en.wikipedia.org/wiki/Protein_Data_Bank PDB] code [http://www.rcsb.org/pdb/explore/explore.do?structureId=4z34 4Z34]) ' scene='72/721543/Overallrainbow2/1'><br />
<br />
<br />
== Introduction ==<br />
Lysophosphatidic Acid Receptor 1 (commonly referred to as LPA<sub>1</sub>) is a [[G protein-coupled receptor]] and one of 6 different LPA receptors (LPA<sub>1</sub>-LPA<sub>6</sub>) that binds the phospholipid derivative [https://en.wikipedia.org/wiki/Lysophosphatidic_acid lysophosphatidic acid (LPA)], a signaling molecule that acts as a potent [https://en.wikipedia.org/wiki/Mitogen mitogen] upon binding to one of its six receptors.<ref name="regpeps">PMID: 26091040</ref> LPA<sub>1</sub> is part of the larger [http://jb.oxfordjournals.org/content/131/6/767 EDG receptor family] which includes the more widely known sphingosine 1-phopshate receptors.<br />
== Structure ==<br />
[[Image:Amphbindingfinal.png|200 px|left|thumb|Figure 1: Electrostatic illustration of the amphipathic binding pocket of the LPA<sub>1</sub> receptor. This binding pocket, located in the interior of the protein, has both polar and nonpolar regions. The blue and red coloration highlight the positively and negatively charged regions, respectively, and the white color shows the nonpolar region of the binding pocket.]]<br />
The LPA<sub>1</sub> receptor protein is composed of 364 amino acids with a mass of approximately 41 kDa. Just as other G-protein coupled receptors, LPA<sub>1</sub> contains seven [http://kinemage.biochem.duke.edu/teaching/anatax/html/anatax.2a.html alpha helices] which make up the seven transmembrane spanning domains with three intracellular loops and three extracellular loops. The amino terminus of this protein is located on the extracellular side of the membrane, while the carboxyl terminus is located on the intracellular side of the membrane.<ref name = 'Hernández-Méndez'>Hernández-Méndez, Aurelio, Rocío Alcántara-Hernández, and J. Adolfo García-Sáinz. "Lysophosphatidic Acid LPA1-3 Receptors: Signaling, Regulation and in Silico Analysis of Their Putative Phosphorylation Sites." Receptors & Clinical Investigation Receptor Clin Invest 1.3 (2014). Web. 15 Feb. 2016.' </ref>. Within these helices is an amphipathic binding pocket which stabilizes the binding of its ligand, LPA.<br />
=== Key Ligand Interactions ===<br />
[[Image:Ligandpocket2.png|200 px|right|thumb|Figure 2: Surface representation of the LPA<sub>1</sub> receptor in tan interacting with its antagonist, ON7, shown in green and red sticks.]]<br />
Three separate interactions with an antagonist of LPA<sub>1</sub>, ON7, help demonstrate the key interactions that stabilize the binding of the LPA phospholipid to this receptor. At the polar region of the binding pocket, the majority of this region is stabilized by <scene name='72/721543/Arg124gln125/3'>Arg124 and Gln125</scene> forming ionic and polar interactions with the carboxylic acid and the hydroxyl group of ON7.<ref name="regpeps">PMID: 26091040</ref> In addition, interplay between <scene name='72/721543/Lys39_and_glu293/7'>Glu293 and Lys39</scene> causes another stabilizing component of the ON7 antagonist. Glu293 forms polar interactions with Lys39, positioning it in close proximity to to the carboxylic acid of ON7, which then interactions with Lys39 via ionic bonding.<ref name="regpeps">PMID: 26091040</ref> While Lys39 is highly conserved among all six LPA receptors, a His40 residue is present that is specific to the LPA<sub>1</sub> receptor. <scene name='72/721543/His40/1'>His40</scene> forms both ionic and polar interactions with the carboxylic acid of ON7. The protonation of this residue has been found to greatly affect the binding affinity of LPA, and is an important link to tumor growth and survival in acidic environments.<ref name="regpeps">PMID: 26091040</ref><br />
<br />
<br />
== Function ==<br />
The LPA<sub>1</sub> receptor is present in nearly all cells and tissues throughout the body, and deletion of the LPA<sub>1</sub> receptor has been found to have physiological effects on every organ system, indicating its wide range of functions. Specifically, this receptor has been found to initiate downstream signaling cascades with three G<sub>α</sub> proteins: G<sub>i/o</sub>, G<sub>q/11</sub>, and G<sub>12/13</sub>. These G<sub>α</sub> proteins begin signaling cascades with molecules such as [https://en.wikipedia.org/wiki/Phospholipase_C phospholipase C] and [[MAPK]] that signal for cell proliferation, survival, and migration. <ref name = 'Yung'>Yung, Y. C., N. C. Stoddard, and J. Chun. "LPA Receptor Signaling: Pharmacology, Physiology, and Pathophysiology." The Journal of Lipid Research 55.7 (2014): 1192-214. Web. 17 Feb. 2016.' </ref>.Despite this receptor being expressed throughout the body, LPA<sub>1</sub> has been found to be expressed highly in neural tissue, aiding in several different neurodevelopmental processes including growth and folding of the [https://www.dartmouth.edu/~rswenson/NeuroSci/chapter_11.html cerebral cortex] and the growth, survival, and migration of neural [https://en.wikipedia.org/wiki/Progenitor_cell progenitor cells] through its different [https://en.wikipedia.org/wiki/G_protein G-protein] regulated pathways.<ref name = 'Chun'>Chun, J., Hla, T., Spiegel, S., and Moolenaar, W.H. “Lysophospholipid Receptors: Signaling and Biochemistry.” John Wiley & Sons, Inc. (2013) pp.i-xviii. 5 Feb. 2016.' </ref>. Finally, LPA1 receptors expressed in neural tissue aid in Schwann cell migration and myelination through a signaling pathway with the [https://en.wikipedia.org/wiki/RAC1 Rac1] G-protein.<ref name="number5">PMID: 24115248</ref>.<br />
<br />
<br />
<br />
== Receptor Comparison ==<br />
<br />
=== Sphingosine 1-Phosphate Receptor ===<br />
LPA<sub>1</sub> belongs to the EDG (endothelial differentiation gene) family of [https://en.wikipedia.org/wiki/Lysophospholipid_receptor lysophospholipid receptors]. This family also includes the [https://en.wikipedia.org/wiki/S1PR1 sphingosine 1-phosphate receptor 1] (S1P<sub>1</sub>), which has many structural similarities to LPA<sub>1</sub>. In fact, the transmembrane regions share a sequence identity of 41%. <ref name = 'Chun, E.'>Chun, E., Thompson, A.A., Lui, W., Roth, C.B., Griffith, M.T., Katritch, V., Kunken, J., Xu, F., Cherezov, V., Hanson, M.A., and Stevens, R.C. “Fusion partner tool chest for the stabilization and crystallization of G protein-coupled receptors.” Structure 20, (2012) 967-976.' </ref> A defining difference between these two receptors is their mode of ligand access to the binding site. Where as the hydrophobic [https://en.wikipedia.org/wiki/Sphingosine-1-phosphate S1P ligand] enters S1P<sub>1</sub> via the membrane, LPA<sub>1</sub> has an extracellular opening that allows LPA access from the extracellular space <ref name="regpeps">PMID: 26091040</ref>. Structural evidence for this altered ligand pathway include global changes in the positioning of the extracellular loops (ECL) and transmembrane helices (TM). Specifically, this includes slight divergence of <scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene>, which is positioned 3 angstroms closer to TMVII compared to S1P<sub>1</sub>, and a repositioning of <scene name='72/721543/Ecl_regions/1'>ECL3</scene>, resulting in a divergence of 8 angstroms from S1P<sub>1</sub> <ref name="regpeps">PMID: 26091040</ref>. This narrowing of the gap between TMI and TMVII blocks membrane ligand access, while the greater distance between ECL3 and the other extracellular loops promotes extracellular access for LPA<sub>1</sub>. Additionally, ECL0 is helical in S1P<sub>1</sub>, but lacks secondary structure in LPA<sub>1</sub>. This increased flexibility that results further promotes favorable access from the extracellular space <ref name="regpeps">PMID: 26091040</ref>.<br />
<br />
<scene name='72/721543/Ecl02ndstructure/1'>TextToBeDisplayed</scene><br />
<br />
[[Image:ECL3DistanceCM.png|200 px|left|thumb|Figure 1: Electrostatic illustration of the amphipathic binding pocket of the LPA<sub>1</sub> receptor. This binding pocket, located in the interior of the protein, has both polar and nonpolar regions. The blue and red coloration highlight the positively and negatively charged regions, respectively, and the white color shows the nonpolar region of the binding pocket.]]<br />
<br />
=== Endocannabinoid Receptor 1 ===<br />
LPA<sub>1</sub> also is closely related to the first of the [http://www.nature.com/ijo/journal/v30/n1s/full/0803272a.html cannabinoid receptors]. This close relation gives CB<sub>1</sub> ([[Cannabinoid Receptor 1]]) the ability to bind to analogs of LPA and vice versa, which opens the possibility of metabolic crosstalk between the two signaling systems. This connection is made possible through ligand phosphorylation and dephosphorylation <ref name="regpeps">PMID: 26091040</ref>. Specifically, complementary access to the LPA<sub>1</sub> binding pocket can be achieved by phosphorylated CB<sub>1</sub> ligand analogs, while complementary access to the CB<sub>1</sub> binding site requires dephosphorylation of LPA<sub>1</sub> ligand analogs. In both cases, a ligand could serve as a primary [https://en.wikipedia.org/wiki/Selective_receptor_modulator receptor modulator] and a simultaneous [https://en.wikipedia.org/wiki/Prodrug prodrug] for a different receptor <ref name="regpeps">PMID: 26091040</ref>.<br />
<br />
<scene name='72/721543/Asp129_and_trp210/2'>Residues Asp129 and Trp210</scene> located within the hydrophobic binding pocket of LPA<sub>1</sub> may share responsibility for the preference for long unsaturated acyl chains. These residues are also interesting in regard to GPCR phylogenic evolution. <ref name="regpeps">PMID: 26091040</ref> Trp210 specifically only occurs in this position in 1% of all class A GPCR receptors and is unique to lysophospholipid and cannabinoid receptors. <ref name = 'Van Durme'>Van Durme, J., Horn, F., Costagliola, S., Vriend, G., and Vassart, G. “GRIS: glycoprotein-hormone receptor information system.” Mol. (2006) Endocrinol. 20, 2247-2255' </ref><br />
<br />
A model for lipid agonist binding generated through molecular modeling was used to dock two of the cannabinoid receptor CB<sub>1</sub>'s most abundant endogenous ligands into the LPA<sub>1</sub> binding pocket. <ref name="regpeps">PMID: 26091040</ref> Rotameric shifts of Trp210 and Trp271 leading to expansion of the binding pocket and the exposure of the π clouds of their indole rings provided favorable interactions with the double bonds of the phosphorylated cannabinoid ligands. This favorable binding provides evidence that the hydrophobic binding pockets of LPA<sub>1</sub> and CB<sub>1</sub> are able to favorably bind the same poly-unsaturated acyl chains with metabolically interconvertible head groups. <ref name="regpeps">PMID: 26091040</ref><br />
[[Image:TrpRotamericShiftsCM.png|200 px|left|thumb|Figure 1: Electrostatic illustration of the amphipathic binding pocket of the LPA<sub>1</sub> receptor. This binding pocket, located in the interior of the protein, has both polar and nonpolar regions. The blue and red coloration highlight the positively and negatively charged regions, respectively, and the white color shows the nonpolar region of the binding pocket.]]<br />
<br />
== Disease Relevance ==<br />
Because LPA<sub>1</sub> is expressed in so many tissues throughout the body, it has been linked to the symptoms and progression of several different diseases and disorders. For example, due to LPA<sub>1</sub>'s role in pain signaling, overexpression of this protein can cause both [https://en.wikipedia.org/wiki/Allodynia allodynia] or [https://en.wikipedia.org/wiki/Hyperalgesia hyperalgesia], common symptoms of multiple sclerosis or strokes. In addition, since LPA<sub>1</sub> helps in the myelination of Schwann cells, mutation of the receptor can also lead to a decrease in [https://en.wikipedia.org/wiki/Prepulse_inhibition prepulse inhibition], a general sign of schizophrenia.<ref name="number6">PMID: 20331961</ref>.Lastly, because of the mitogen signaling activity of LPA<sub>1</sub>, abnormal expression or mutation of this receptor has been linked to tumor growth, survival, and migration in both liver and lung tumors. As recently discussed, the His40 on LPA<sub>1</sub>, when protonated, increased LPA binding affinity is increase by up to 1kcal/mol. Because of this, in an acidic environment that is typically produced by [https://en.wikipedia.org/wiki/Tumor_hypoxia hypoxic tumors] creating lactic acid, LPA<sub>1</sub> activity is increased, allowing these tumors to continue to proliferate, migrate, and survive.<ref name="number7">PMID: 24367336</ref>. In contrast, the LPA<sub>1</sub> receptor has also been found to induce protective functions in the presence of a particular illness. For example, in patients with heart disease, LPA<sub>1</sub> has been found to communicate with [[PI3K]], [https://en.wikipedia.org/wiki/Protein_kinase_B PKB], and [[ERK]] to create a hypertrophic response in the heart in order to offset reduced heart contractions.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Chandler Mitchellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1172&diff=2586745Sandbox Reserved 11722016-04-12T13:24:03Z<p>Chandler Mitchell: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Central_Metabolism}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Lysophosphatidic Acid Receptor 1==<br />
<StructureSection load='4z34' size='340' side='right' caption='Cartoon representation of the LPA1 protein and its antagonist, ON7, colored in white. ([https://en.wikipedia.org/wiki/Protein_Data_Bank PDB] code [http://www.rcsb.org/pdb/explore/explore.do?structureId=4z34 4Z34]) ' scene='72/721543/Overallrainbow/1'><br />
<br />
<br />
== Introduction ==<br />
Lysophosphatidic Acid Receptor 1 (commonly referred to as LPA<sub>1</sub>) is a [[G protein-coupled receptor]] and one of 6 different LPA receptors (LPA<sub>1</sub>-LPA<sub>6</sub>) that binds the phospholipid derivative [https://en.wikipedia.org/wiki/Lysophosphatidic_acid lysophosphatidic acid (LPA)], a signaling molecule that acts as a potent [https://en.wikipedia.org/wiki/Mitogen mitogen] upon binding to one of its six receptors.<ref name="regpeps">PMID: 26091040</ref> LPA<sub>1</sub> is part of the larger [http://jb.oxfordjournals.org/content/131/6/767 EDG receptor family] which includes the more widely known sphingosine 1-phopshate receptors.<br />
== Structure ==<br />
[[Image:Amphbindingfinal.png|200 px|left|thumb|Figure 1: Electrostatic illustration of the amphipathic binding pocket of the LPA<sub>1</sub> receptor. This binding pocket, located in the interior of the protein, has both polar and nonpolar regions. The blue and red coloration highlight the positively and negatively charged regions, respectively, and the white color shows the nonpolar region of the binding pocket.]]<br />
The LPA<sub>1</sub> receptor protein is composed of 364 amino acids with a mass of approximately 41 kDa. Just as other G-protein coupled receptors, LPA<sub>1</sub> contains seven [http://kinemage.biochem.duke.edu/teaching/anatax/html/anatax.2a.html alpha helices] which make up the seven transmembrane spanning domains with three intracellular loops and three extracellular loops. The amino terminus of this protein is located on the extracellular side of the membrane, while the carboxyl terminus is located on the intracellular side of the membrane.<ref name = 'Hernández-Méndez'>Hernández-Méndez, Aurelio, Rocío Alcántara-Hernández, and J. Adolfo García-Sáinz. "Lysophosphatidic Acid LPA1-3 Receptors: Signaling, Regulation and in Silico Analysis of Their Putative Phosphorylation Sites." Receptors & Clinical Investigation Receptor Clin Invest 1.3 (2014). Web. 15 Feb. 2016.' </ref>. Within these helices is an amphipathic binding pocket which stabilizes the binding of its ligand, LPA.<br />
=== Key Ligand Interactions ===<br />
[[Image:Ligandpocket2.png|200 px|right|thumb|Figure 2: Surface representation of the LPA<sub>1</sub> receptor in tan interacting with its antagonist, ON7, shown in green and red sticks.]]<br />
Three separate interactions with an antagonist of LPA<sub>1</sub>, ON7, help demonstrate the key interactions that stabilize the binding of the LPA phospholipid to this receptor. At the polar region of the binding pocket, the majority of this region is stabilized by <scene name='72/721543/Arg124gln125/1'>Arg124 and Gln125</scene> forming ionic and polar interactions with the carboxylic acid and the hydroxyl group of ON7.<ref name="regpeps">PMID: 26091040</ref> In addition, interplay between <scene name='72/721543/Lys39_and_glu293/4'>Glu293 and Lys39</scene> causes another stabilizing component of the ON7 antagonist. Glu293 forms polar interactions with Lys39, positioning it in close proximity to to the carboxylic acid of ON7, which then interactions with Lys39 via ionic bonding.<ref name="regpeps">PMID: 26091040</ref> While Lys39 is highly conserved among all six LPA receptors, a His40 residue is present that is specific to the LPA<sub>1</sub> receptor. <scene name='72/721543/His40/1'>His40</scene> forms both ionic and polar interactions with the carboxylic acid of ON7. The protonation of this residue has been found to greatly affect the binding affinity of LPA, and is an important link to tumor growth and survival in acidic environments.<ref name="regpeps">PMID: 26091040</ref><br />
<br />
<br />
== Function ==<br />
The LPA<sub>1</sub> receptor is present in nearly all cells and tissues throughout the body, and deletion of the LPA<sub>1</sub> receptor has been found to have physiological effects on every organ system, indicating its wide range of functions. Specifically, this receptor has been found to initiate downstream signaling cascades with three G<sub>α</sub> proteins: G<sub>i/o</sub>, G<sub>q/11</sub>, and G<sub>12/13</sub>. These G<sub>α</sub> proteins begin signaling cascades with molecules such as [https://en.wikipedia.org/wiki/Phospholipase_C phospholipase C] and [[MAPK]] that signal for cell proliferation, survival, and migration. <ref name = 'Yung'>Yung, Y. C., N. C. Stoddard, and J. Chun. "LPA Receptor Signaling: Pharmacology, Physiology, and Pathophysiology." The Journal of Lipid Research 55.7 (2014): 1192-214. Web. 17 Feb. 2016.' </ref>.Despite this receptor being expressed throughout the body, LPA<sub>1</sub> has been found to be expressed highly in neural tissue, aiding in several different neurodevelopmental processes including growth and folding of the [https://www.dartmouth.edu/~rswenson/NeuroSci/chapter_11.html cerebral cortex] and the growth, survival, and migration of neural [https://en.wikipedia.org/wiki/Progenitor_cell progenitor cells] through its different [https://en.wikipedia.org/wiki/G_protein G-protein] regulated pathways.<ref name = 'Chun'>Chun, J., Hla, T., Spiegel, S., and Moolenaar, W.H. “Lysophospholipid Receptors: Signaling and Biochemistry.” John Wiley & Sons, Inc. (2013) pp.i-xviii. 5 Feb. 2016.' </ref>. Finally, LPA1 receptors expressed in neural tissue aid in Schwann cell migration and myelination through a signaling pathway with the [https://en.wikipedia.org/wiki/RAC1 Rac1] G-protein.<ref name="number5">PMID: 24115248</ref>.<br />
<br />
<br />
<br />
== Receptor Comparison ==<br />
<br />
=== Sphingosine 1-Phosphate Receptor ===<br />
LPA<sub>1</sub> belongs to the EDG (endothelial differentiation gene) family of [https://en.wikipedia.org/wiki/Lysophospholipid_receptor lysophospholipid receptors]. This family also includes the [https://en.wikipedia.org/wiki/S1PR1 sphingosine 1-phosphate receptor 1] (S1P<sub>1</sub>), which has many structural similarities to LPA<sub>1</sub>. In fact, the transmembrane regions share a sequence identity of 41%. <ref name = 'Chun, E.'>Chun, E., Thompson, A.A., Lui, W., Roth, C.B., Griffith, M.T., Katritch, V., Kunken, J., Xu, F., Cherezov, V., Hanson, M.A., and Stevens, R.C. “Fusion partner tool chest for the stabilization and crystallization of G protein-coupled receptors.” Structure 20, (2012) 967-976.' </ref> A defining difference between these two receptors is their mode of ligand access to the binding site. Where as the hydrophobic [https://en.wikipedia.org/wiki/Sphingosine-1-phosphate S1P ligand] enters S1P<sub>1</sub> via the membrane, LPA<sub>1</sub> has an extracellular opening that allows LPA access from the extracellular space <ref name="regpeps">PMID: 26091040</ref>. Structural evidence for this altered ligand pathway include global changes in the positioning of the extracellular loops (ECL) and transmembrane helices (TM). Specifically, this includes slight divergence of <scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene>, which is positioned 3 angstroms closer to TMVII compared to S1P<sub>1</sub>, and a repositioning of <scene name='72/721543/Ecl_regions/1'>ECL3</scene>, resulting in a divergence of 8 angstroms from S1P<sub>1</sub> <ref name="regpeps">PMID: 26091040</ref>. This narrowing of the gap between TMI and TMVII blocks membrane ligand access, while the greater distance between ECL3 and the other extracellular loops promotes extracellular access for LPA<sub>1</sub>. Additionally, ECL0 is helical in S1P<sub>1</sub>, but lacks secondary structure in LPA<sub>1</sub>. This increased flexibility that results further promotes favorable access from the extracellular space <ref name="regpeps">PMID: 26091040</ref>.<br />
<br />
[[Image:ECL3DistanceCM.png|200 px|left|thumb|Figure 1: Electrostatic illustration of the amphipathic binding pocket of the LPA<sub>1</sub> receptor. This binding pocket, located in the interior of the protein, has both polar and nonpolar regions. The blue and red coloration highlight the positively and negatively charged regions, respectively, and the white color shows the nonpolar region of the binding pocket.]]<br />
<br />
=== Endocannabinoid Receptor 1 ===<br />
LPA<sub>1</sub> also is closely related to the first of the [http://www.nature.com/ijo/journal/v30/n1s/full/0803272a.html cannabinoid receptors]. This close relation gives CB<sub>1</sub> ([[Cannabinoid Receptor 1]]) the ability to bind to analogs of LPA and vice versa, which opens the possibility of metabolic crosstalk between the two signaling systems. This connection is made possible through ligand phosphorylation and dephosphorylation <ref name="regpeps">PMID: 26091040</ref>. Specifically, complementary access to the LPA<sub>1</sub> binding pocket can be achieved by phosphorylated CB<sub>1</sub> ligand analogs, while complementary access to the CB<sub>1</sub> binding site requires dephosphorylation of LPA<sub>1</sub> ligand analogs. In both cases, a ligand could serve as a primary [https://en.wikipedia.org/wiki/Selective_receptor_modulator receptor modulator] and a simultaneous [https://en.wikipedia.org/wiki/Prodrug prodrug] for a different receptor <ref name="regpeps">PMID: 26091040</ref>.<br />
<br />
<scene name='72/721543/Asp129_and_trp210/2'>Residues Asp129 and Trp210</scene> located within the hydrophobic binding pocket of LPA<sub>1</sub> may share responsibility for the preference for long unsaturated acyl chains. These residues are also interesting in regard to GPCR phylogenic evolution. <ref name="regpeps">PMID: 26091040</ref> Trp210 specifically only occurs in this position in 1% of all class A GPCR receptors and is unique to lysophospholipid and cannabinoid receptors. <ref name = 'Van Durme'>Van Durme, J., Horn, F., Costagliola, S., Vriend, G., and Vassart, G. “GRIS: glycoprotein-hormone receptor information system.” Mol. (2006) Endocrinol. 20, 2247-2255' </ref><br />
<br />
A model for lipid agonist binding generated through molecular modeling was used to dock two of the cannabinoid receptor CB<sub>1</sub>'s most abundant endogenous ligands into the LPA<sub>1</sub> binding pocket. <ref name="regpeps">PMID: 26091040</ref> Rotameric shifts of Trp210 and Trp271 leading to expansion of the binding pocket and the exposure of the π clouds of their indole rings provided favorable interactions with the double bonds of the phosphorylated cannabinoid ligands. This favorable binding provides evidence that the hydrophobic binding pockets of LPA<sub>1</sub> and CB<sub>1</sub> are able to favorably bind the same poly-unsaturated acyl chains with metabolically interconvertible head groups. <ref name="regpeps">PMID: 26091040</ref><br />
[[Image:TrpRotamericShiftsCM.png|200 px|left|thumb|Figure 1: Electrostatic illustration of the amphipathic binding pocket of the LPA<sub>1</sub> receptor. This binding pocket, located in the interior of the protein, has both polar and nonpolar regions. The blue and red coloration highlight the positively and negatively charged regions, respectively, and the white color shows the nonpolar region of the binding pocket.]]<br />
<br />
== Disease Relevance ==<br />
Because LPA<sub>1</sub> is expressed in so many tissues throughout the body, it has been linked to the symptoms and progression of several different diseases and disorders. For example, due to LPA<sub>1</sub>'s role in pain signaling, overexpression of this protein can cause both [https://en.wikipedia.org/wiki/Allodynia allodynia] or [https://en.wikipedia.org/wiki/Hyperalgesia hyperalgesia], common symptoms of multiple sclerosis or strokes. In addition, since LPA<sub>1</sub> helps in the myelination of Schwann cells, mutation of the receptor can also lead to a decrease in [https://en.wikipedia.org/wiki/Prepulse_inhibition prepulse inhibition], a general sign of schizophrenia.<ref name="number6">PMID: 20331961</ref>.Lastly, because of the mitogen signaling activity of LPA<sub>1</sub>, abnormal expression or mutation of this receptor has been linked to tumor growth, survival, and migration in both liver and lung tumors. As recently discussed, the His40 on LPA<sub>1</sub>, when protonated, increased LPA binding affinity is increase by up to 1kcal/mol. Because of this, in an acidic environment that is typically produced by [https://en.wikipedia.org/wiki/Tumor_hypoxia hypoxic tumors] creating lactic acid, LPA<sub>1</sub> activity is increased, allowing these tumors to continue to proliferate, migrate, and survive.<ref name="number7">PMID: 24367336</ref>. In contrast, the LPA<sub>1</sub> receptor has also been found to induce protective functions in the presence of a particular illness. For example, in patients with heart disease, LPA<sub>1</sub> has been found to communicate with [[PI3K]], [https://en.wikipedia.org/wiki/Protein_kinase_B PKB], and [[ERK]] to create a hypertrophic response in the heart in order to offset reduced heart contractions.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Chandler Mitchellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1172&diff=2586738Sandbox Reserved 11722016-04-12T13:19:00Z<p>Chandler Mitchell: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Central_Metabolism}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Lysophosphatidic Acid Receptor 1==<br />
<StructureSection load='4z34' size='340' side='right' caption='Cartoon representation of the LPA1 protein and its antagonist, ON7, colored in white. ([https://en.wikipedia.org/wiki/Protein_Data_Bank PDB] code [http://www.rcsb.org/pdb/explore/explore.do?structureId=4z34 4Z34]) ' scene='72/721543/Overallrainbow/1'><br />
<br />
<br />
== Introduction ==<br />
Lysophosphatidic Acid Receptor 1 (commonly referred to as LPA<sub>1</sub>) is a [[G protein-coupled receptor]] and one of 6 different LPA receptors (LPA<sub>1</sub>-LPA<sub>6</sub>) that binds the phospholipid derivative [https://en.wikipedia.org/wiki/Lysophosphatidic_acid lysophosphatidic acid (LPA)], a signaling molecule that acts as a potent [https://en.wikipedia.org/wiki/Mitogen mitogen] upon binding to one of its six receptors.<ref name="regpeps">PMID: 26091040</ref> LPA<sub>1</sub> is part of the larger [http://jb.oxfordjournals.org/content/131/6/767 EDG receptor family] which includes the more widely known sphingosine 1-phopshate receptors.<br />
== Structure ==<br />
[[Image:Amphbindingfinal.png|200 px|left|thumb|Figure 1: Electrostatic illustration of the amphipathic binding pocket of the LPA<sub>1</sub> receptor. This binding pocket, located in the interior of the protein, has both polar and nonpolar regions. The blue and red coloration highlight the positively and negatively charged regions, respectively, and the white color shows the nonpolar region of the binding pocket.]]<br />
The LPA<sub>1</sub> receptor protein is composed of 364 amino acids with a mass of approximately 41 kDa. Just as other G-protein coupled receptors, LPA<sub>1</sub> contains seven [http://kinemage.biochem.duke.edu/teaching/anatax/html/anatax.2a.html alpha helices] which make up the seven transmembrane spanning domains with three intracellular loops and three extracellular loops. The amino terminus of this protein is located on the extracellular side of the membrane, while the carboxyl terminus is located on the intracellular side of the membrane.<ref name = 'Hernández-Méndez'>Hernández-Méndez, Aurelio, Rocío Alcántara-Hernández, and J. Adolfo García-Sáinz. "Lysophosphatidic Acid LPA1-3 Receptors: Signaling, Regulation and in Silico Analysis of Their Putative Phosphorylation Sites." Receptors & Clinical Investigation Receptor Clin Invest 1.3 (2014). Web. 15 Feb. 2016.' </ref>. Within these helices is an amphipathic binding pocket which stabilizes the binding of its ligand, LPA.<br />
=== Key Ligand Interactions ===<br />
[[Image:Ligandpocket2.png|200 px|right|thumb|Figure 2: Surface representation of the LPA<sub>1</sub> receptor in tan interacting with its antagonist, ON7, shown in green and red sticks.]]<br />
Three separate interactions with an antagonist of LPA<sub>1</sub>, ON7, help demonstrate the key interactions that stabilize the binding of the LPA phospholipid to this receptor. At the polar region of the binding pocket, the majority of this region is stabilized by <scene name='72/721543/Arg124gln125/1'>Arg124 and Gln125</scene> forming ionic and polar interactions with the carboxylic acid and the hydroxyl group of ON7.<ref name="regpeps">PMID: 26091040</ref> In addition, interplay between <scene name='72/721543/Lys39_and_glu293/4'>Glu293 and Lys39</scene> causes another stabilizing component of the ON7 antagonist. Glu293 forms polar interactions with Lys39, positioning it in close proximity to to the carboxylic acid of ON7, which then interactions with Lys39 via ionic bonding.<ref name="regpeps">PMID: 26091040</ref> While Lys39 is highly conserved among all six LPA receptors, a His40 residue is present that is specific to the LPA<sub>1</sub> receptor. <scene name='72/721543/His40/1'>His40</scene> forms both ionic and polar interactions with the carboxylic acid of ON7. The protonation of this residue has been found to greatly affect the binding affinity of LPA, and is an important link to tumor growth and survival in acidic environments.<ref name="regpeps">PMID: 26091040</ref><br />
<br />
<br />
== Function ==<br />
The LPA<sub>1</sub> receptor is present in nearly all cells and tissues throughout the body, and deletion of the LPA<sub>1</sub> receptor has been found to have physiological effects on every organ system, indicating its wide range of functions. Specifically, this receptor has been found to initiate downstream signaling cascades with three G<sub>α</sub> proteins: G<sub>i/o</sub>, G<sub>q/11</sub>, and G<sub>12/13</sub>. These G<sub>α</sub> proteins begin signaling cascades with molecules such as [https://en.wikipedia.org/wiki/Phospholipase_C phospholipase C] and [[MAPK]] that signal for cell proliferation, survival, and migration. <ref name = 'Yung'>Yung, Y. C., N. C. Stoddard, and J. Chun. "LPA Receptor Signaling: Pharmacology, Physiology, and Pathophysiology." The Journal of Lipid Research 55.7 (2014): 1192-214. Web. 17 Feb. 2016.' </ref>.Despite this receptor being expressed throughout the body, LPA<sub>1</sub> has been found to be expressed highly in neural tissue, aiding in several different neurodevelopmental processes including growth and folding of the [https://www.dartmouth.edu/~rswenson/NeuroSci/chapter_11.html cerebral cortex] and the growth, survival, and migration of neural [https://en.wikipedia.org/wiki/Progenitor_cell progenitor cells] through its different [https://en.wikipedia.org/wiki/G_protein G-protein] regulated pathways.<ref name = 'Chun'>Chun, J., Hla, T., Spiegel, S., and Moolenaar, W.H. “Lysophospholipid Receptors: Signaling and Biochemistry.” John Wiley & Sons, Inc. (2013) pp.i-xviii. 5 Feb. 2016.' </ref>. Finally, LPA1 receptors expressed in neural tissue aid in Schwann cell migration and myelination through a signaling pathway with the [https://en.wikipedia.org/wiki/RAC1 Rac1] G-protein.<ref name="number5">PMID: 24115248</ref>.<br />
<br />
<br />
== Disease Relevance ==<br />
Because LPA<sub>1</sub> is expressed in so many tissues throughout the body, it has been linked to the symptoms and progression of several different diseases and disorders. For example, due to LPA<sub>1</sub>'s role in pain signaling, overexpression of this protein can cause both [https://en.wikipedia.org/wiki/Allodynia allodynia] or [https://en.wikipedia.org/wiki/Hyperalgesia hyperalgesia], common symptoms of multiple sclerosis or strokes. In addition, since LPA<sub>1</sub> helps in the myelination of Schwann cells, mutation of the receptor can also lead to a decrease in [https://en.wikipedia.org/wiki/Prepulse_inhibition prepulse inhibition], a general sign of schizophrenia.<ref name="number6">PMID: 20331961</ref>.Lastly, because of the mitogen signaling activity of LPA<sub>1</sub>, abnormal expression or mutation of this receptor has been linked to tumor growth, survival, and migration in both liver and lung tumors. As recently discussed, the His40 on LPA<sub>1</sub>, when protonated, increased LPA binding affinity is increase by up to 1kcal/mol. Because of this, in an acidic environment that is typically produced by [https://en.wikipedia.org/wiki/Tumor_hypoxia hypoxic tumors] creating lactic acid, LPA<sub>1</sub> activity is increased, allowing these tumors to continue to proliferate, migrate, and survive.<ref name="number7">PMID: 24367336</ref>. In contrast, the LPA<sub>1</sub> receptor has also been found to induce protective functions in the presence of a particular illness. For example, in patients with heart disease, LPA<sub>1</sub> has been found to communicate with [[PI3K]], [https://en.wikipedia.org/wiki/Protein_kinase_B PKB], and [[ERK]] to create a hypertrophic response in the heart in order to offset reduced heart contractions.<br />
<br />
== Receptor Comparison ==<br />
<br />
=== Sphingosine 1-Phosphate Receptor ===<br />
LPA<sub>1</sub> belongs to the EDG (endothelial differentiation gene) family of [https://en.wikipedia.org/wiki/Lysophospholipid_receptor lysophospholipid receptors]. This family also includes the [https://en.wikipedia.org/wiki/S1PR1 sphingosine 1-phosphate receptor 1] (S1P<sub>1</sub>), which has many structural similarities to LPA<sub>1</sub>. In fact, the transmembrane regions share a sequence identity of 41%. <ref name = 'Chun, E.'>Chun, E., Thompson, A.A., Lui, W., Roth, C.B., Griffith, M.T., Katritch, V., Kunken, J., Xu, F., Cherezov, V., Hanson, M.A., and Stevens, R.C. “Fusion partner tool chest for the stabilization and crystallization of G protein-coupled receptors.” Structure 20, (2012) 967-976.' </ref> A defining difference between these two receptors is their mode of ligand access to the binding site. Where as the hydrophobic [https://en.wikipedia.org/wiki/Sphingosine-1-phosphate S1P ligand] enters S1P<sub>1</sub> via the membrane, LPA<sub>1</sub> has an extracellular opening that allows LPA access from the extracellular space <ref name="regpeps">PMID: 26091040</ref>. Structural evidence for this altered ligand pathway include global changes in the positioning of the extracellular loops (ECL) and transmembrane helices (TM). Specifically, this includes slight divergence of <scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene>, which is positioned 3 angstroms closer to TMVII compared to S1P<sub>1</sub>, and a repositioning of <scene name='72/721543/Ecl_regions/1'>ECL3</scene>, resulting in a divergence of 8 angstroms from S1P<sub>1</sub> <ref name="regpeps">PMID: 26091040</ref>. This narrowing of the gap between TMI and TMVII blocks membrane ligand access, while the greater distance between ECL3 and the other extracellular loops promotes extracellular access for LPA<sub>1</sub>. Additionally, ECL0 is helical in S1P<sub>1</sub>, but lacks secondary structure in LPA<sub>1</sub>. This increased flexibility that results further promotes favorable access from the extracellular space <ref name="regpeps">PMID: 26091040</ref>.<br />
<br />
[[Image:ECL3DistanceCM.png|200 px|left|thumb|Figure 1: Electrostatic illustration of the amphipathic binding pocket of the LPA<sub>1</sub> receptor. This binding pocket, located in the interior of the protein, has both polar and nonpolar regions. The blue and red coloration highlight the positively and negatively charged regions, respectively, and the white color shows the nonpolar region of the binding pocket.]]<br />
<br />
=== Endocannabinoid Receptor 1 ===<br />
LPA<sub>1</sub> also is closely related to the first of the [http://www.nature.com/ijo/journal/v30/n1s/full/0803272a.html cannabinoid receptors]. This close relation gives CB<sub>1</sub> ([[Cannabinoid Receptor 1]]) the ability to bind to analogs of LPA and vice versa, which opens the possibility of metabolic crosstalk between the two signaling systems. This connection is made possible through ligand phosphorylation and dephosphorylation <ref name="regpeps">PMID: 26091040</ref>. Specifically, complementary access to the LPA<sub>1</sub> binding pocket can be achieved by phosphorylated CB<sub>1</sub> ligand analogs, while complementary access to the CB<sub>1</sub> binding site requires dephosphorylation of LPA<sub>1</sub> ligand analogs. In both cases, a ligand could serve as a primary [https://en.wikipedia.org/wiki/Selective_receptor_modulator receptor modulator] and a simultaneous [https://en.wikipedia.org/wiki/Prodrug prodrug] for a different receptor <ref name="regpeps">PMID: 26091040</ref>.<br />
<br />
<scene name='72/721543/Asp129_and_trp210/2'>Residues Asp129 and Trp210</scene> located within the hydrophobic binding pocket of LPA<sub>1</sub> may share responsibility for the preference for long unsaturated acyl chains. These residues are also interesting in regard to GPCR phylogenic evolution. <ref name="regpeps">PMID: 26091040</ref> Trp210 specifically only occurs in this position in 1% of all class A GPCR receptors and is unique to lysophospholipid and cannabinoid receptors. <ref name = 'Van Durme'>Van Durme, J., Horn, F., Costagliola, S., Vriend, G., and Vassart, G. “GRIS: glycoprotein-hormone receptor information system.” Mol. (2006) Endocrinol. 20, 2247-2255' </ref><br />
<br />
A model for lipid agonist binding generated through molecular modeling was used to dock two of the cannabinoid receptor CB<sub>1</sub>'s most abundant endogenous ligands into the LPA<sub>1</sub> binding pocket. <ref name="regpeps">PMID: 26091040</ref> Rotameric shifts of Trp210 and Trp271 leading to expansion of the binding pocket and the exposure of the π clouds of their indole rings provided favorable interactions with the double bonds of the phosphorylated cannabinoid ligands. This favorable binding provides evidence that the hydrophobic binding pockets of LPA<sub>1</sub> and CB<sub>1</sub> are able to favorably bind the same poly-unsaturated acyl chains with metabolically interconvertible head groups. <ref name="regpeps">PMID: 26091040</ref><br />
[[Image:TrpRotamericShiftsCM.png|200 px|left|thumb|Figure 1: Electrostatic illustration of the amphipathic binding pocket of the LPA<sub>1</sub> receptor. This binding pocket, located in the interior of the protein, has both polar and nonpolar regions. The blue and red coloration highlight the positively and negatively charged regions, respectively, and the white color shows the nonpolar region of the binding pocket.]]<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Chandler Mitchellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1172&diff=2586730Sandbox Reserved 11722016-04-12T13:15:44Z<p>Chandler Mitchell: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Central_Metabolism}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Lysophosphatidic Acid Receptor 1==<br />
<StructureSection load='4z34' size='340' side='right' caption='Cartoon representation of the LPA1 protein and its antagonist, ON7, colored in white. ([https://en.wikipedia.org/wiki/Protein_Data_Bank PDB] code [http://www.rcsb.org/pdb/explore/explore.do?structureId=4z34 4Z34]) ' scene='72/721543/Overallrainbow/1'><br />
<br />
<br />
== Introduction ==<br />
Lysophosphatidic Acid Receptor 1 (commonly referred to as LPA<sub>1</sub>) is a [[G protein-coupled receptor]] and one of 6 different LPA receptors (LPA<sub>1</sub>-LPA<sub>6</sub>) that binds the phospholipid derivative [https://en.wikipedia.org/wiki/Lysophosphatidic_acid lysophosphatidic acid (LPA)], a signaling molecule that acts as a potent [https://en.wikipedia.org/wiki/Mitogen mitogen] upon binding to one of its six receptors.<ref name="regpeps">PMID: 26091040</ref> LPA<sub>1</sub> is part of the larger [http://jb.oxfordjournals.org/content/131/6/767 EDG receptor family] which includes the more widely known sphingosine 1-phopshate receptors.<br />
== Structure ==<br />
[[Image:Amphbindingfinal.png|200 px|left|thumb|Figure 1: Electrostatic illustration of the amphipathic binding pocket of the LPA<sub>1</sub> receptor. This binding pocket, located in the interior of the protein, has both polar and nonpolar regions. The blue and red coloration highlight the positively and negatively charged regions, respectively, and the white color shows the nonpolar region of the binding pocket.]]<br />
The LPA<sub>1</sub> receptor protein is composed of 364 amino acids with a mass of approximately 41 kDa. Just as other G-protein coupled receptors, LPA<sub>1</sub> contains seven [http://kinemage.biochem.duke.edu/teaching/anatax/html/anatax.2a.html alpha helices] which make up the seven transmembrane spanning domains with three intracellular loops and three extracellular loops. The amino terminus of this protein is located on the extracellular side of the membrane, while the carboxyl terminus is located on the intracellular side of the membrane.<ref name = 'Hernández-Méndez'>Hernández-Méndez, Aurelio, Rocío Alcántara-Hernández, and J. Adolfo García-Sáinz. "Lysophosphatidic Acid LPA1-3 Receptors: Signaling, Regulation and in Silico Analysis of Their Putative Phosphorylation Sites." Receptors & Clinical Investigation Receptor Clin Invest 1.3 (2014). Web. 15 Feb. 2016.' </ref>. Within these helices is an amphipathic binding pocket which stabilizes the binding of its ligand, LPA.<br />
=== Key Ligand Interactions ===<br />
[[Image:Ligandpocket2.png|200 px|right|thumb|Figure 2: Surface representation of the LPA<sub>1</sub> receptor in tan interacting with its antagonist, ON7, shown in green and red sticks.]]<br />
Three separate interactions with an antagonist of LPA<sub>1</sub>, ON7, help demonstrate the key interactions that stabilize the binding of the LPA phospholipid to this receptor. At the polar region of the binding pocket, the majority of this region is stabilized by <scene name='72/721543/Arg124gln125/1'>Arg124 and Gln125</scene> forming ionic and polar interactions with the carboxylic acid and the hydroxyl group of ON7.<ref name="regpeps">PMID: 26091040</ref> In addition, interplay between <scene name='72/721543/Lys39_and_glu293/4'>Glu293 and Lys39</scene> causes another stabilizing component of the ON7 antagonist. Glu293 forms polar interactions with Lys39, positioning it in close proximity to to the carboxylic acid of ON7, which then interactions with Lys39 via ionic bonding.<ref name="regpeps">PMID: 26091040</ref> While Lys39 is highly conserved among all six LPA receptors, a His40 residue is present that is specific to the LPA<sub>1</sub> receptor. <scene name='72/721543/His40/1'>His40</scene> forms both ionic and polar interactions with the carboxylic acid of ON7. The protonation of this residue has been found to greatly affect the binding affinity of LPA, and is an important link to tumor growth and survival in acidic environments.<ref name="regpeps">PMID: 26091040</ref><br />
<br />
<br />
== Function ==<br />
The LPA<sub>1</sub> receptor is present in nearly all cells and tissues throughout the body, and deletion of the LPA<sub>1</sub> receptor has been found to have physiological effects on every organ system, indicating its wide range of functions. Specifically, this receptor has been found to initiate downstream signaling cascades with three G<sub>α</sub> proteins: G<sub>i/o</sub>, G<sub>q/11</sub>, and G<sub>12/13</sub>. These G<sub>α</sub> proteins begin signaling cascades with molecules such as [https://en.wikipedia.org/wiki/Phospholipase_C phospholipase C] and [[MAPK]] that signal for cell proliferation, survival, and migration. <ref name = 'Yung'>Yung, Y. C., N. C. Stoddard, and J. Chun. "LPA Receptor Signaling: Pharmacology, Physiology, and Pathophysiology." The Journal of Lipid Research 55.7 (2014): 1192-214. Web. 17 Feb. 2016.' </ref>.Despite this receptor being expressed throughout the body, LPA<sub>1</sub> has been found to be expressed highly in neural tissue, aiding in several different neurodevelopmental processes including growth and folding of the [https://www.dartmouth.edu/~rswenson/NeuroSci/chapter_11.html cerebral cortex] and the growth, survival, and migration of neural [https://en.wikipedia.org/wiki/Progenitor_cell progenitor cells] through its different [https://en.wikipedia.org/wiki/G_protein G-protein] regulated pathways.<ref name = 'Chun'>Chun, J., Hla, T., Spiegel, S., and Moolenaar, W.H. “Lysophospholipid Receptors: Signaling and Biochemistry.” John Wiley & Sons, Inc. (2013) pp.i-xviii. 5 Feb. 2016.' </ref>. Finally, LPA1 receptors expressed in neural tissue aid in Schwann cell migration and myelination through a signaling pathway with the [https://en.wikipedia.org/wiki/RAC1 Rac1] G-protein.<ref name="number5">PMID: 24115248</ref>.<br />
<br />
<br />
== Disease Relevance ==<br />
Because LPA<sub>1</sub> is expressed in so many tissues throughout the body, it has been linked to the symptoms and progression of several different diseases and disorders. For example, due to LPA<sub>1</sub>'s role in pain signaling, overexpression of this protein can cause both [https://en.wikipedia.org/wiki/Allodynia allodynia] or [https://en.wikipedia.org/wiki/Hyperalgesia hyperalgesia], common symptoms of multiple sclerosis or strokes. In addition, since LPA<sub>1</sub> helps in the myelination of Schwann cells, mutation of the receptor can also lead to a decrease in [https://en.wikipedia.org/wiki/Prepulse_inhibition prepulse inhibition], a general sign of schizophrenia.<ref name="number6">PMID: 20331961</ref>.Lastly, because of the mitogen signaling activity of LPA<sub>1</sub>, abnormal expression or mutation of this receptor has been linked to tumor growth, survival, and migration in both liver and lung tumors. As recently discussed, the His40 on LPA<sub>1</sub>, when protonated, increased LPA binding affinity is increase by up to 1kcal/mol. Because of this, in an acidic environment that is typically produced by [https://en.wikipedia.org/wiki/Tumor_hypoxia hypoxic tumors] creating lactic acid, LPA<sub>1</sub> activity is increased, allowing these tumors to continue to proliferate, migrate, and survive.<ref name="number7">PMID: 24367336</ref>. In contrast, the LPA<sub>1</sub> receptor has also been found to induce protective functions in the presence of a particular illness. For example, in patients with heart disease, LPA<sub>1</sub> has been found to communicate with [[PI3K]], [https://en.wikipedia.org/wiki/Protein_kinase_B PKB], and [[ERK]] to create a hypertrophic response in the heart in order to offset reduced heart contractions.<br />
<br />
== Receptor Comparison ==<br />
<br />
=== Sphingosine 1-Phosphate Receptor ===<br />
LPA<sub>1</sub> belongs to the EDG (endothelial differentiation gene) family of [https://en.wikipedia.org/wiki/Lysophospholipid_receptor lysophospholipid receptors]. This family also includes the [https://en.wikipedia.org/wiki/S1PR1 sphingosine 1-phosphate receptor 1] (S1P<sub>1</sub>), which has many structural similarities to LPA<sub>1</sub>. In fact, the transmembrane regions share a sequence identity of 41%. <ref name = 'Chun, E.'>Chun, E., Thompson, A.A., Lui, W., Roth, C.B., Griffith, M.T., Katritch, V., Kunken, J., Xu, F., Cherezov, V., Hanson, M.A., and Stevens, R.C. “Fusion partner tool chest for the stabilization and crystallization of G protein-coupled receptors.” Structure 20, (2012) 967-976.' </ref> A defining difference between these two receptors is their mode of ligand access to the binding site. Where as the hydrophobic [https://en.wikipedia.org/wiki/Sphingosine-1-phosphate S1P ligand] enters S1P<sub>1</sub> via the membrane, LPA<sub>1</sub> has an extracellular opening that allows LPA access from the extracellular space <ref name="regpeps">PMID: 26091040</ref>. Structural evidence for this altered ligand pathway include global changes in the positioning of the extracellular loops (ECL) and transmembrane helices (TM). Specifically, this includes slight divergence of <scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene>, which is positioned 3 angstroms closer to TMVII compared to S1P<sub>1</sub>, and a repositioning of <scene name='72/721543/Ecl_regions/1'>ECL3</scene>, resulting in a divergence of 8 angstroms from S1P<sub>1</sub> <ref name="regpeps">PMID: 26091040</ref>. This narrowing of the gap between TMI and TMVII blocks membrane ligand access, while the greater distance between ECL3 and the other extracellular loops promotes extracellular access for LPA<sub>1</sub>. Additionally, ECL0 is helical in S1P<sub>1</sub>, but lacks secondary structure in LPA<sub>1</sub>. This increased flexibility that results further promotes favorable access from the extracellular space <ref name="regpeps">PMID: 26091040</ref>.<br />
<br />
[[Image:ECL3DistanceCM.png|200 px|left|thumb|Figure 1: Electrostatic illustration of the amphipathic binding pocket of the LPA<sub>1</sub> receptor. This binding pocket, located in the interior of the protein, has both polar and nonpolar regions. The blue and red coloration highlight the positively and negatively charged regions, respectively, and the white color shows the nonpolar region of the binding pocket.]]<br />
<br />
=== Endocannabinoid Receptor 1 ===<br />
LPA<sub>1</sub> also is closely related to the first of the [http://www.nature.com/ijo/journal/v30/n1s/full/0803272a.html cannabinoid receptors]. This close relation gives CB<sub>1</sub> ([[Cannabinoid Receptor 1]]) the ability to bind to analogs of LPA and vice versa, which opens the possibility of metabolic crosstalk between the two signaling systems. This connection is made possible through ligand phosphorylation and dephosphorylation <ref name="regpeps">PMID: 26091040</ref>. Specifically, complementary access to the LPA<sub>1</sub> binding pocket can be achieved by phosphorylated CB<sub>1</sub> ligand analogs, while complementary access to the CB<sub>1</sub> binding site requires dephosphorylation of LPA<sub>1</sub> ligand analogs. In both cases, a ligand could serve as a primary [https://en.wikipedia.org/wiki/Selective_receptor_modulator receptor modulator] and a simultaneous [https://en.wikipedia.org/wiki/Prodrug prodrug] for a different receptor <ref name="regpeps">PMID: 26091040</ref>.<br />
<br />
<scene name='72/721543/Asp129_and_trp210/2'>Residues Asp129 and Trp210</scene> located within the hydrophobic binding pocket of LPA<sub>1</sub> may share responsibility for the preference for long unsaturated acyl chains. These residues are also interesting in regard to GPCR phylogenic evolution. <ref name="regpeps">PMID: 26091040</ref> Trp210 specifically only occurs in this position in 1% of all class A GPCR receptors and is unique to lysophospholipid and cannabinoid receptors. <ref name = 'Van Durme'>Van Durme, J., Horn, F., Costagliola, S., Vriend, G., and Vassart, G. “GRIS: glycoprotein-hormone receptor information system.” Mol. (2006) Endocrinol. 20, 2247-2255' </ref><br />
<br />
A model for lipid agonist binding generated through molecular modeling was used to dock two of the cannabinoid receptor CB<sub>1</sub>'s most abundant endogenous ligands into the LPA<sub>1</sub> binding pocket. <ref name="regpeps">PMID: 26091040</ref> Rotameric shifts of Trp210 and Trp271 leading to expansion of the binding pocket and the exposure of the π clouds of their indole rings provided favorable interactions with the double bonds of the phosphorylated cannabinoid ligands. This favorable binding provides evidence that the hydrophobic binding pockets of LPA<sub>1</sub> and CB<sub>1</sub> are able to favorably bind the same poly-unsaturated acyl chains with metabolically interconvertible head groups. <ref name="regpeps">PMID: 26091040</ref><br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Chandler Mitchellhttps://proteopedia.org/index.php?title=File:ECL3DistanceCM.png&diff=2586724File:ECL3DistanceCM.png2016-04-12T13:11:09Z<p>Chandler Mitchell: </p>
<hr />
<div></div>Chandler Mitchellhttps://proteopedia.org/index.php?title=File:TrpRotamericShiftsCM.png&diff=2586720File:TrpRotamericShiftsCM.png2016-04-12T13:09:47Z<p>Chandler Mitchell: </p>
<hr />
<div></div>Chandler Mitchellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1172&diff=2585138Sandbox Reserved 11722016-03-30T19:02:49Z<p>Chandler Mitchell: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Central_Metabolism}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Lysophosphatidic Acid Receptor 1==<br />
<StructureSection load='4z34' size='340' side='right' caption='Cartoon representation of the LPA1 protein and its antagonist, ON7, colored in white. ([https://en.wikipedia.org/wiki/Protein_Data_Bank PDB] code [http://www.rcsb.org/pdb/explore/explore.do?structureId=4z34 4Z34]) ' scene='72/721543/Overallrainbow/1'><br />
<br />
<br />
== Introduction ==<br />
Lysophosphatidic Acid Receptor 1 (commonly referred to as LPA<sub>1</sub>) is a [[G protein-coupled receptor]] and one of 6 different LPA receptors (LPA<sub>1</sub>-LPA<sub>6</sub>) that binds the phospholipid derivative [https://en.wikipedia.org/wiki/Lysophosphatidic_acid lysophosphatidic acid (LPA)], a signaling molecule that acts as a potent [https://en.wikipedia.org/wiki/Mitogen mitogen] upon binding to one of its six receptors.<ref name="regpeps">PMID: 26091040</ref> LPA<sub>1</sub> is part of the larger [http://jb.oxfordjournals.org/content/131/6/767 EDG receptor family] which includes the more widely known sphingosine 1-phopshate receptors.<br />
== Structure ==<br />
[[Image:ABP.png|250 px|left|thumb|Electrostatic illustration of the amphipathic binding pocket of the LPA<sub>1</sub> receptor.]]<br />
The LPA<sub>1</sub> receptor protein is composed of 364 amino acids with a mass of approximately 41 kDa. Just as other G-protein coupled receptors, LPA<sub>1</sub> contains seven [http://kinemage.biochem.duke.edu/teaching/anatax/html/anatax.2a.html alpha helices] which make up the seven transmembrane spanning domains with three intracellular loops and three extracellular loops. The amino terminus of this protein is located on the extracellular side of the membrane, while the carboxyl terminus is located on the intracellular side of the membrane.<ref name = 'Hernández-Méndez'>Hernández-Méndez, Aurelio, Rocío Alcántara-Hernández, and J. Adolfo García-Sáinz. "Lysophosphatidic Acid LPA1-3 Receptors: Signaling, Regulation and in Silico Analysis of Their Putative Phosphorylation Sites." Receptors & Clinical Investigation Receptor Clin Invest 1.3 (2014). Web. 15 Feb. 2016.' </ref>. Within these helices is an amphipathic binding pocket which stabilizes the binding of its ligand, LPA.<br />
=== Key Ligand Interactions ===<br />
[[Image:ON7.png|250 px|right|thumb|Overall structure of the LPA<sub>1</sub> receptor in tan interacting with its antagonist, ON7, shown in green and red sticks.]]<br />
Three separate interactions with an antagonist of LPA<sub>1</sub>, ON7, help demonstrate the key interactions that stabilize the binding of the LPA phospholipid to this receptor. At the polar region of the binding pocket, the majority of this region is stabilized by <scene name='72/721543/Arg124gln125/1'>Arg124 and Gln125</scene> forming ionic and polar interactions with the carboxylic acid and the hydroxyl group of ON7.<ref name="regpeps">PMID: 26091040</ref> In addition, interplay between <scene name='72/721543/Lys39_and_glu293/4'>Glu293 and Lys39</scene> causes another stabilizing component of the ON7 antagonist. Glu293 forms polar interactions with Lys39, positioning it in close proximity to to the carboxylic acid of ON7, which then interactions with Lys39 via ionic bonding.<ref name="regpeps">PMID: 26091040</ref> While Lys39 is highly conserved among all six LPA receptors, a His40 residue is present that is specific to the LPA<sub>1</sub> receptor. <scene name='72/721543/His40/1'>His40</scene> forms both ionic and polar interactions with the carboxylic acid of ON7. The protonation of this residue has been found to greatly affect the binding affinity of LPA, and is an important link to tumor growth and survival in acidic environments.<ref name="regpeps">PMID: 26091040</ref><br />
<br />
<br />
== Function ==<br />
The LPA<sub>1</sub> receptor is present in nearly all cells and tissues throughout the body, and deletion of the LPA<sub>1</sub> receptor has been found to have physiological effects on every organ system, indicating its wide range of functions. Specifically, this receptor has been found to initiate downstream signaling cascades with three G<sub>α</sub> proteins: G<sub>i/o</sub>, G<sub>q/11</sub>, and G<sub>12/13</sub>. These G<sub>α</sub> proteins begin signaling cascades with molecules such as [https://en.wikipedia.org/wiki/Phospholipase_C phospholipase C] and [[MAPK]] that signal for cell proliferation, survival, and migration. <ref name = 'Yung'>Yung, Y. C., N. C. Stoddard, and J. Chun. "LPA Receptor Signaling: Pharmacology, Physiology, and Pathophysiology." The Journal of Lipid Research 55.7 (2014): 1192-214. Web. 17 Feb. 2016.' </ref>.Despite this receptor being expressed throughout the body, LPA<sub>1</sub> has been found to be expressed highly in neural tissue, aiding in several different neurodevelopmental processes including growth and folding of the [https://www.dartmouth.edu/~rswenson/NeuroSci/chapter_11.html cerebral cortex] and the growth, survival, and migration of neural [https://en.wikipedia.org/wiki/Progenitor_cell progenitor cells] through its different [https://en.wikipedia.org/wiki/G_protein link G-protein] regulated pathways.<ref name = 'Chun'>Chun, J., Hla, T., Spiegel, S., and Moolenaar, W.H. “Lysophospholipid Receptors: Signaling and Biochemistry.” John Wiley & Sons, Inc. (2013) pp.i-xviii. 5 Feb. 2016.' </ref>. Finally, LPA1 receptors expressed in neural tissue aid in Schwann cell migration and myelination through a signaling pathway with the [https://en.wikipedia.org/wiki/RAC1 Rac1] G-protein.<ref name="number5">PMID: 24115248</ref>.<br />
<br />
<br />
== Disease Relevance ==<br />
Because LPA<sub>1</sub> is expressed in so many tissues throughout the body, it has been linked to the symptoms and progression of several different diseases and disorders. For example, due to LPA<sub>1</sub>'s role in pain signaling, overexpression of this protein can cause both [https://en.wikipedia.org/wiki/Allodynia allodynia] or [https://en.wikipedia.org/wiki/Hyperalgesia hyperalgesia], common symptoms of multiple sclerosis or strokes. In addition, since LPA<sub>1</sub> helps in the myelination of Schwann cells, mutation of the receptor can also lead to a decrease in [https://en.wikipedia.org/wiki/Prepulse_inhibition prepulse inhibition], a general sign of schizophrenia.<ref name="number6">PMID: 20331961</ref>.Lastly, because of the mitogen signaling activity of LPA<sub>1</sub>, abnormal expression or mutation of this receptor has been linked to tumor growth, survival, and migration in both liver and lung tumors. As recently discussed, the His40 on LPA<sub>1</sub>, when protonated, increased LPA binding affinity is increase by up to 1kcal/mol. Because of this, in an acidic environment that is typically produced by [https://en.wikipedia.org/wiki/Tumor_hypoxia hypoxic tumors] creating lactic acid, LPA<sub>1</sub> activity is increased, allowing these tumors to continue to proliferate, migrate, and survive.<ref name="number7">PMID: 24367336</ref>. In contrast, the LPA<sub>1</sub> receptor has also been found to induce protective functions in the presence of a particular illness. For example, in patients with heart disease, LPA<sub>1</sub> has been found to communicate with [[PI3K]], [https://en.wikipedia.org/wiki/Protein_kinase_B PKB], and [[ERK]] to create a hypertrophic response in the heart in order to offset reduced heart contractions.<br />
<br />
== Receptor Comparison ==<br />
<br />
=== Sphingosine 1-Phosphate Receptor ===<br />
LPA<sub>1</sub> belongs to the EDG (endothelial differentiation gene) family of [https://en.wikipedia.org/wiki/Lysophospholipid_receptor lysophospholipid receptors]. This family also includes the [https://en.wikipedia.org/wiki/S1PR1 sphingosine 1-phosphate receptor 1] (S1P<sub>1</sub>), which has many structural similarities to LPA<sub>1</sub>. In fact, the transmembrane regions share a sequence identity of 41%. <ref name = 'Chun, E.'>Chun, E., Thompson, A.A., Lui, W., Roth, C.B., Griffith, M.T., Katritch, V., Kunken, J., Xu, F., Cherezov, V., Hanson, M.A., and Stevens, R.C. “Fusion partner tool chest for the stabilization and crystallization of G protein-coupled receptors.” Structure 20, (2012) 967-976.' </ref> A defining difference between these two receptors is their mode of ligand access to the binding site. Where as the hydrophobic [https://en.wikipedia.org/wiki/Sphingosine-1-phosphate S1P ligand] enters S1P<sub>1</sub> via the membrane, LPA<sub>1</sub> has an extracellular opening that allows LPA access from the extracellular space <ref name="regpeps">PMID: 26091040</ref>. Structural evidence for this altered ligand pathway include global changes in the positioning of the extracellular loops (ECL) and transmembrane helices (TM). Specifically, this includes slight divergence of <scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene>, which is positioned 3 angstroms closer to TMVII compared to S1P<sub>1</sub>, and a repositioning of <scene name='72/721543/Ecl_regions/1'>ECL3</scene>, resulting in a divergence of 8 angstroms from S1P<sub>1</sub> <ref name="regpeps">PMID: 26091040</ref>. This narrowing of the gap between TMI and TMVII blocks membrane ligand access, while the greater distance between ECL3 and the other extracellular loops promotes extracellular access for LPA<sub>1</sub>. Additionally, ECL0 is helical in S1P<sub>1</sub>, but lacks secondary structure in LPA<sub>1</sub>. This increased flexibility that results further promotes favorable access from the extracellular space <ref name="regpeps">PMID: 26091040</ref>.<br />
<br />
<br />
<br />
=== Endocannabinoid Receptor 1 ===<br />
LPA<sub>1</sub> also is closely related to the first of the [http://www.nature.com/ijo/journal/v30/n1s/full/0803272a.html cannabinoid receptors]. This close relation gives CB<sub>1</sub> ([[Cannabinoid Receptor 1]]) the ability to bind to analogs of LPA and vice versa, which opens the possibility of metabolic crosstalk between the two signaling systems. This connection is made possible through ligand phosphorylation and dephosphorylation <ref name="regpeps">PMID: 26091040</ref>. Specifically, complementary access to the LPA<sub>1</sub> binding pocket can be achieved by phosphorylated CB<sub>1</sub> ligand analogs, while complementary access to the CB<sub>1</sub> binding site requires dephosphorylation of LPA<sub>1</sub> ligand analogs. In both cases, a ligand could serve as a primary [https://en.wikipedia.org/wiki/Selective_receptor_modulator receptor modulator] and a simultaneous [https://en.wikipedia.org/wiki/Prodrug prodrug] for a different receptor <ref name="regpeps">PMID: 26091040</ref>.<br />
<br />
<scene name='72/721543/Asp129_and_trp210/2'>Residues Asp129 and Trp210</scene> located within the hydrophobic binding pocket of LPA<sub>1</sub> may share responsibility for the preference for long unsaturated acyl chains. These residues are also interesting in regard to GPCR phylogenic evolution. <ref name="regpeps">PMID: 26091040</ref> Trp210 specifically only occurs in this position in 1% of all class A GPCR receptors and is unique to lysophospholipid and cannabinoid receptors. <ref name = 'Van Durme'>Van Durme, J., Horn, F., Costagliola, S., Vriend, G., and Vassart, G. “GRIS: glycoprotein-hormone receptor information system.” Mol. (2006) Endocrinol. 20, 2247-2255' </ref><br />
<br />
A model for lipid agonist binding generated through molecular modeling was used to dock two of the cannabinoid receptor CB<sub>1</sub>'s most abundant endogenous ligands into the LPA<sub>1</sub> binding pocket. <ref name="regpeps">PMID: 26091040</ref> Rotameric shifts of Trp210 and Trp271 leading to expansion of the binding pocket and the exposure of the π clouds of their indole rings provided favorable interactions with the double bonds of the phosphorylated cannabinoid ligands. This favorable binding provides evidence that the hydrophobic binding pockets of LPA<sub>1</sub> and CB<sub>1</sub> are able to favorably bind the same poly-unsaturated acyl chains with metabolically interconvertible head groups. <ref name="regpeps">PMID: 26091040</ref><br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Chandler Mitchellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1172&diff=2585137Sandbox Reserved 11722016-03-30T19:01:28Z<p>Chandler Mitchell: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Central_Metabolism}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Lysophosphatidic Acid Receptor 1==<br />
<StructureSection load='4z34' size='340' side='right' caption='Cartoon representation of the LPA1 protein and its antagonist, ON7, colored in white. ([https://en.wikipedia.org/wiki/Protein_Data_Bank PDB] code [http://www.rcsb.org/pdb/explore/explore.do?structureId=4z34 4Z34]) ' scene='72/721543/Overallrainbow/1'><br />
<br />
<br />
== Introduction ==<br />
Lysophosphatidic Acid Receptor 1 (commonly referred to as LPA<sub>1</sub>) is a [[G protein-coupled receptor]] and one of 6 different LPA receptors (LPA<sub>1</sub>-LPA<sub>6</sub>) that binds the phospholipid derivative [https://en.wikipedia.org/wiki/Lysophosphatidic_acid lysophosphatidic acid (LPA)], a signaling molecule that acts as a potent [https://en.wikipedia.org/wiki/Mitogen mitogen] upon binding to one of its six receptors.<ref name="regpeps">PMID: 26091040</ref> LPA<sub>1</sub> is part of the larger [http://jb.oxfordjournals.org/content/131/6/767 EDG receptor family] which includes the more widely known sphingosine 1-phopshate receptors.<br />
== Structure ==<br />
[[Image:ABP.png|250 px|left|thumb|Electrostatic illustration of the amphipathic binding pocket of the LPA<sub>1</sub> receptor.]]<br />
The LPA<sub>1</sub> receptor protein is composed of 364 amino acids with a mass of approximately 41 kDa. Just as other G-protein coupled receptors, LPA<sub>1</sub> contains seven [http://kinemage.biochem.duke.edu/teaching/anatax/html/anatax.2a.html alpha helices] which make up the seven transmembrane spanning domains with three intracellular loops and three extracellular loops. The amino terminus of this protein is located on the extracellular side of the membrane, while the carboxyl terminus is located on the intracellular side of the membrane.<ref name = 'Hernández-Méndez'>Hernández-Méndez, Aurelio, Rocío Alcántara-Hernández, and J. Adolfo García-Sáinz. "Lysophosphatidic Acid LPA1-3 Receptors: Signaling, Regulation and in Silico Analysis of Their Putative Phosphorylation Sites." Receptors & Clinical Investigation Receptor Clin Invest 1.3 (2014). Web. 15 Feb. 2016.' </ref>. Within these helices is an amphipathic binding pocket which stabilizes the binding of its ligand, LPA.<br />
=== Key Ligand Interactions ===<br />
[[Image:ON7.png|250 px|right|thumb|Overall structure of the LPA<sub>1</sub> receptor in tan interacting with its antagonist, ON7, shown in green and red sticks.]]<br />
Three separate interactions with an antagonist of LPA<sub>1</sub>, ON7, help demonstrate the key interactions that stabilize the binding of the LPA phospholipid to this receptor. At the polar region of the binding pocket, the majority of this region is stabilized by <scene name='72/721543/Arg124gln125/1'>Arg124 and Gln125</scene> forming ionic and polar interactions with the carboxylic acid and the hydroxyl group of ON7.<ref name="regpeps">PMID: 26091040</ref> In addition, interplay between <scene name='72/721543/Lys39_and_glu293/4'>Glu293 and Lys39</scene> causes another stabilizing component of the ON7 antagonist. Glu293 forms polar interactions with Lys39, positioning it in close proximity to to the carboxylic acid of ON7, which then interactions with Lys39 via ionic bonding.<ref name="regpeps">PMID: 26091040</ref> While Lys39 is highly conserved among all six LPA receptors, a His40 residue is present that is specific to the LPA<sub>1</sub> receptor. <scene name='72/721543/His40/1'>His40</scene> forms both ionic and polar interactions with the carboxylic acid of ON7. The protonation of this residue has been found to greatly affect the binding affinity of LPA, and is an important link to tumor growth and survival in acidic environments.<ref name="regpeps">PMID: 26091040</ref><br />
<br />
<br />
== Function ==<br />
The LPA<sub>1</sub> receptor is present in nearly all cells and tissues throughout the body, and deletion of the LPA<sub>1</sub> receptor has been found to have physiological effects on every organ system, indicating its wide range of functions. Specifically, this receptor has been found to initiate downstream signaling cascades with three G<sub>α</sub> proteins: G<sub>i/o</sub>, G<sub>q/11</sub>, and G<sub>12/13</sub>. These G<sub>α</sub> proteins begin signaling cascades with molecules such as [https://en.wikipedia.org/wiki/Phospholipase_C phospholipase C] and [[MAPK]] that signal for cell proliferation, survival, and migration. <ref name = 'Yung'>Yung, Y. C., N. C. Stoddard, and J. Chun. "LPA Receptor Signaling: Pharmacology, Physiology, and Pathophysiology." The Journal of Lipid Research 55.7 (2014): 1192-214. Web. 17 Feb. 2016.' </ref>.Despite this receptor being expressed throughout the body, LPA<sub>1</sub> has been found to be expressed highly in neural tissue, aiding in several different neurodevelopmental processes including growth and folding of the [https://www.dartmouth.edu/~rswenson/NeuroSci/chapter_11.html cerebral cortex] and the growth, survival, and migration of neural [https://en.wikipedia.org/wiki/Progenitor_cell progenitor cells] through its different [https://en.wikipedia.org/wiki/G_protein link G-protein] regulated pathways.<ref name = 'Chun'>Chun, J., Hla, T., Spiegel, S., and Moolenaar, W.H. “Lysophospholipid Receptors: Signaling and Biochemistry.” John Wiley & Sons, Inc. (2013) pp.i-xviii. 5 Feb. 2016.' </ref>. Finally, LPA1 receptors expressed in neural tissue aid in Schwann cell migration and myelination through a signaling pathway with the [https://en.wikipedia.org/wiki/RAC1 Rac1] G-protein.<ref name="number5">PMID: 24115248</ref>.<br />
<br />
<br />
== Disease Relevance ==<br />
Because LPA<sub>1</sub> is expressed in so many tissues throughout the body, it has been linked to the symptoms and progression of several different diseases and disorders. For example, due to LPA<sub>1</sub>'s role in pain signaling, overexpression of this protein can cause both [https://en.wikipedia.org/wiki/Allodynia allodynia] or [https://en.wikipedia.org/wiki/Hyperalgesia hyperalgesia], common symptoms of multiple sclerosis or strokes. In addition, since LPA<sub>1</sub> helps in the myelination of Schwann cells, mutation of the receptor can also lead to a decrease in [https://en.wikipedia.org/wiki/Prepulse_inhibition prepulse inhibition], a general sign of schizophrenia.<ref name="number6">PMID: 20331961</ref>.Lastly, because of the mitogen signaling activity of LPA<sub>1</sub>, abnormal expression or mutation of this receptor has been linked to tumor growth, survival, and migration in both liver and lung tumors. As recently discussed, the His40 on LPA<sub>1</sub>, when protonated, increased LPA binding affinity is increase by up to 1kcal/mol. Because of this, in an acidic environment that is typically produced by [https://en.wikipedia.org/wiki/Tumor_hypoxia hypoxic tumors] creating lactic acid, LPA<sub>1</sub> activity is increased, allowing these tumors to continue to proliferate, migrate, and survive.<ref name="number7">PMID: 24367336</ref>. In contrast, the LPA<sub>1</sub> receptor has also been found to induce protective functions in the presence of a particular illness. For example, in patients with heart disease, LPA<sub>1</sub> has been found to communicate with [[PI3K]], [https://en.wikipedia.org/wiki/Protein_kinase_B PKB], and [[ERK]] to create a hypertrophic response in the heart in order to offset reduced heart contractions.<br />
<br />
== Receptor Comparison ==<br />
<br />
=== Sphingosine 1-Phosphate Receptor ===<br />
LPA<sub>1</sub> belongs to the EDG (endothelial differentiation gene) family of [https://en.wikipedia.org/wiki/Lysophospholipid_receptor lysophospholipid receptors]. This family also includes the [https://en.wikipedia.org/wiki/S1PR1 sphingosine 1-phosphate receptor 1] (S1P<sub>1</sub>), which has many structural similarities to LPA<sub>1</sub>. In fact, the transmembrane regions share a sequence identity of 41%. <ref name = 'Chun, E.'>Chun, E., Thompson, A.A., Lui, W., Roth, C.B., Griffith, M.T., Katritch, V., Kunken, J., Xu, F., Cherezov, V., Hanson, M.A., and Stevens, R.C. “Fusion partner tool chest for the stabilization and crystallization of G protein-coupled receptors.” Structure 20, (2012) 967-976.' </ref> A defining difference between these two receptors is their mode of ligand access to the binding site. Where as the hydrophobic [https://en.wikipedia.org/wiki/Sphingosine-1-phosphate S1P ligand] enters S1P<sub>1</sub> via the membrane, LPA<sub>1</sub> has an extracellular opening that allows LPA access from the extracellular space <ref name="regpeps">PMID: 26091040</ref>. Structural evidence for this altered ligand pathway include global changes in the positioning of the extracellular loops (ECL) and transmembrane helices (TM). Specifically, this includes slight divergence of <scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene>, which is positioned 3 angstroms closer to TMVII compared to S1P<sub>1</sub>, and a repositioning of <scene name='72/721543/Ecl_regions/1'>ECL3</scene>, resulting in a divergence of 8 angstroms from S1P<sub>1</sub> <ref name="regpeps">PMID: 26091040</ref>. This narrowing of the gap between TMI and TMVII blocks membrane ligand access, while the greater distance between ECL3 and the other extracellular loops promotes extracellular access for LPA<sub>1</sub>. Additionally, ECL0 is helical in S1P<sub>1</sub>, but lacks secondary structure in LPA<sub>1</sub>. This increased flexibility that results further promotes favorable access from the extracellular space <ref name="regpeps">PMID: 26091040</ref>.<br />
<br />
<br />
<br />
=== Endocannabinoid Receptor 1 ===<br />
LPA<sub>1</sub> also is closely related to the [http://www.nature.com/ijo/journal/v30/n1s/full/0803272a.html cannabinoid receptor]. This close relation gives CB<sub>1</sub> ([[Cannabinoid Receptor 1]]) the ability to bind to analogs of LPA and vice versa, which opens the possibility of metabolic crosstalk between the two signaling systems. This connection is made possible through ligand phosphorylation and dephosphorylation <ref name="regpeps">PMID: 26091040</ref>. Specifically, complementary access to the LPA<sub>1</sub> binding pocket can be achieved by phosphorylated CB<sub>1</sub> ligand analogs, while complementary access to the CB<sub>1</sub> binding site requires dephosphorylation of LPA<sub>1</sub> ligand analogs. In both cases, a ligand could serve as a primary [https://en.wikipedia.org/wiki/Selective_receptor_modulator receptor modulator] and a simultaneous [https://en.wikipedia.org/wiki/Prodrug prodrug] for a different receptor <ref name="regpeps">PMID: 26091040</ref>.<br />
<br />
<scene name='72/721543/Asp129_and_trp210/2'>Residues Asp129 and Trp210</scene> located within the hydrophobic binding pocket of LPA<sub>1</sub> may share responsibility for the preference for long unsaturated acyl chains. These residues are also interesting in regard to GPCR phylogenic evolution. <ref name="regpeps">PMID: 26091040</ref> Trp210 specifically only occurs in this position in 1% of all class A GPCR receptors and is unique to lysophospholipid and cannabinoid receptors. <ref name = 'Van Durme'>Van Durme, J., Horn, F., Costagliola, S., Vriend, G., and Vassart, G. “GRIS: glycoprotein-hormone receptor information system.” Mol. (2006) Endocrinol. 20, 2247-2255' </ref><br />
<br />
A model for lipid agonist binding generated through molecular modeling was used to dock two of the cannabinoid receptor CB<sub>1</sub>'s most abundant endogenous ligands into the LPA<sub>1</sub> binding pocket. <ref name="regpeps">PMID: 26091040</ref> Rotameric shifts of Trp210 and Trp271 leading to expansion of the binding pocket and the exposure of the π clouds of their indole rings provided favorable interactions with the double bonds of the phosphorylated cannabinoid ligands. This favorable binding provides evidence that the hydrophobic binding pockets of LPA<sub>1</sub> and CB<sub>1</sub> are able to favorably bind the same poly-unsaturated acyl chains with metabolically interconvertible head groups. <ref name="regpeps">PMID: 26091040</ref><br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Chandler Mitchellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1172&diff=2585108Sandbox Reserved 11722016-03-30T16:38:52Z<p>Chandler Mitchell: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Central_Metabolism}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Lysophosphatidic Acid Receptor 1==<br />
<StructureSection load='4z34' size='340' side='right' caption='Cartoon representation of the LPA1 protein and its antagonist, ON7, colored in white. ([https://en.wikipedia.org/wiki/Protein_Data_Bank PDB] code [http://www.rcsb.org/pdb/explore/explore.do?structureId=4z34 4Z34]) ' scene='72/721543/Overallrainbow/1'><br />
<br />
<br />
== Introduction ==<br />
Lysophosphatidic Acid Receptor 1 (commonly referred to as LPA<sub>1</sub>) is a [[G protein-coupled receptor]] and one of 6 different LPA receptors (LPA<sub>1</sub>-LPA<sub>6</sub>) that bind the phospholipid derivative [https://en.wikipedia.org/wiki/Lysophosphatidic_acid lysophosphatidic acid (LPA)], a signaling molecule that acts as a potent [https://en.wikipedia.org/wiki/Mitogen mitogen] upon binding to one of its six receptors.<ref name="regpeps">PMID: 26091040</ref>. LPA<sub>1</sub> is part of the larger [http://jb.oxfordjournals.org/content/131/6/767 EDG receptor family] which includes the more widely known sphingosine 1-phopshate receptors.<br />
== Structure ==<br />
[[Image:ABP.png|250 px|left|thumb|Electrostatic illustration of the amphipathic binding pocket of the LPA<sub>1</sub> receptor.]]<br />
The LPA<sub>1</sub> receptor protein is composed of 364 amino acids with a mass of approximately 41 kDa. Just as other G-protein coupled receptors, LPA<sub>1</sub> contains seven [http://kinemage.biochem.duke.edu/teaching/anatax/html/anatax.2a.html alpha helices] which make up the seven transmembrane spanning domains with three intracellular loops and three extracellular loops. The amino terminus of this protein is located on the extracellular side of the membrane, while the carboxyl terminus is located on the intracellular side of the membrane.<ref name = 'Hernández-Méndez'>Hernández-Méndez, Aurelio, Rocío Alcántara-Hernández, and J. Adolfo García-Sáinz. "Lysophosphatidic Acid LPA1-3 Receptors: Signaling, Regulation and in Silico Analysis of Their Putative Phosphorylation Sites." Receptors & Clinical Investigation Receptor Clin Invest 1.3 (2014). Web. 15 Feb. 2016.' </ref>. Within these helices is an amphipathic binding pocket which stabilizes the binding of its ligand, LPA.<br />
=== Key Ligand Interactions ===<br />
[[Image:ON7.png|250 px|right|thumb|Overall structure of the LPA<sub>1</sub> receptor in tan interacting with its antagonist, ON7, shown in green and red sticks.]]<br />
Three separate interactions with an antagonist of LPA<sub>1</sub>, ON7, help demonstrate the key interactions that stabilize the binding of the LPA phospholipid to this receptor. At the polar region of the binding pocket, the majority of this region is stabilized by <scene name='72/721543/Arg124gln125/1'>Arg124 and Gln125</scene> forming ionic and polar interactions with the carboxylic acid and the hydroxyl group of ON7.<ref name="regpeps">PMID: 26091040</ref> In addition, interplay between <scene name='72/721543/Lys39_and_glu293/4'>Glu293 and Lys39</scene> causes another stabilizing component of the ON7 antagonist. Glu293 forms polar interactions with Lys39, positioning it in close proximity to to the carboxylic acid of ON7, which then interactions with Lys39 via ionic bonding.<ref name="regpeps">PMID: 26091040</ref> While Lys39 is highly conserved among all six LPA receptors, a His40 residue is present that is specific to the LPA<sub>1</sub> receptor. <scene name='72/721543/His40/1'>His40</scene> forms both ionic and polar interactions with the carboxylic acid of ON7. The protonation of this residue has been found to greatly affect the binding affinity of LPA, and is an important link to tumor growth and survival in acidic environments.<ref name="regpeps">PMID: 26091040</ref><br />
<br />
<br />
== Function ==<br />
The LPA<sub>1</sub> receptor is present in nearly all cells and tissues throughout the body, and deletion of the LPA<sub>1</sub> receptor has been found to have physiological effects on every organ system, indicating its wide range of functions. Specifically, this receptor has been found to initiate downstream signaling cascades with three G<sub>α</sub> proteins: G<sub>i/o</sub>, G<sub>q/11</sub>, and G<sub>12/13</sub>. These G<sub>α</sub> proteins begin signaling cascades with molecules such as [https://en.wikipedia.org/wiki/Phospholipase_C phospholipase C] and [[MAPK]] that signal for cell proliferation, survival, and migration. <ref name = 'Yung'>Yung, Y. C., N. C. Stoddard, and J. Chun. "LPA Receptor Signaling: Pharmacology, Physiology, and Pathophysiology." The Journal of Lipid Research 55.7 (2014): 1192-214. Web. 17 Feb. 2016.' </ref>.Despite this receptor being expressed throughout the body, LPA<sub>1</sub> has been found to be expressed highly in neural tissue, aiding in several different neurodevelopmental processes including growth and folding of the [https://www.dartmouth.edu/~rswenson/NeuroSci/chapter_11.html cerebral cortex] and the growth, survival, and migration of neural [https://en.wikipedia.org/wiki/Progenitor_cell progenitor cells] through its different [https://en.wikipedia.org/wiki/G_protein link G-protein] regulated pathways.<ref name = 'Chun'>Chun, J., Hla, T., Spiegel, S., and Moolenaar, W.H. “Lysophospholipid Receptors: Signaling and Biochemistry.” John Wiley & Sons, Inc. (2013) pp.i-xviii. 5 Feb. 2016.' </ref>. Finally, LPA1 receptors expressed in neural tissue aid in Schwann cell migration and myelination through a signaling pathway with the [https://en.wikipedia.org/wiki/RAC1 Rac1] G-protein.<ref name="number5">PMID: 24115248</ref>.<br />
<br />
<br />
== Disease Relevance ==<br />
Because LPA<sub>1</sub> is expressed in so many tissues throughout the body, it has been linked to the symptoms and progression of several different diseases and disorders. For example, due to LPA<sub>1</sub>'s role in pain signaling, overexpression of this protein can cause both [https://en.wikipedia.org/wiki/Allodynia allodynia] or [https://en.wikipedia.org/wiki/Hyperalgesia hyperalgesia], common symptoms of multiple sclerosis or strokes. In addition, since LPA<sub>1</sub> helps in the myelination of Schwann cells, mutation of the receptor can also lead to a decrease in [https://en.wikipedia.org/wiki/Prepulse_inhibition prepulse inhibition], a general sign of schizophrenia.<ref name="number6">PMID: 20331961</ref>.Lastly, because of the mitogen signaling activity of LPA<sub>1</sub>, abnormal expression or mutation of this receptor has been linked to tumor growth, survival, and migration in both liver and lung tumors. As recently discussed, the His40 on LPA<sub>1</sub>, when protonated, increased LPA binding affinity is increase by up to 1kcal/mol. Because of this, in an acidic environment that is typically produced by [https://en.wikipedia.org/wiki/Tumor_hypoxia hypoxic tumors] creating lactic acid, LPA<sub>1</sub> activity is increased, allowing these tumors to continue to proliferate, migrate, and survive.<ref name="number7">PMID: 24367336</ref>. In contrast, the LPA<sub>1</sub> receptor has also been found to induce protective functions in the presence of a particular illness. For example, in patients with heart disease, LPA<sub>1</sub> has been found to communicate with [[PI3K]], [https://en.wikipedia.org/wiki/Protein_kinase_B PKB], and [[ERK]] to create a hypertrophic response in the heart in order to offset reduced heart contractions.<br />
<br />
== Receptor Comparison ==<br />
<br />
=== Sphingosine 1-Phosphate Receptor ===<br />
LPA<sub>1</sub> belongs to the EDG (endothelial differentiation gene) family of [https://en.wikipedia.org/wiki/Lysophospholipid_receptor lysophospholipid receptors]. This family also includes the [https://en.wikipedia.org/wiki/S1PR1 sphingosine 1-phosphate receptor 1] (S1P<sub>1</sub>), which has many structural similarities to LPA<sub>1</sub>. In fact, the transmembrane regions share a sequence identity of 41%. A defining difference between these two receptors is their mode of ligand access to the binding site. Where as the hydrophobic [https://en.wikipedia.org/wiki/Sphingosine-1-phosphate S1P ligand] enters S1P<sub>1</sub> via the membrane, LPA<sub>1</sub> has an extracellular opening that allows LPA access from the extracellular space <ref name="regpeps">PMID: 26091040</ref>. Structural evidence for this altered ligand pathway include global changes in the positioning of the extracellular loops (ECL) and transmembrane helices (TM). Specifically, this includes slight divergence of <scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene>, which is positioned 3 angstroms closer to TMVII compared to S1P<sub>1</sub>, and a repositioning of <scene name='72/721543/Ecl_regions/1'>ECL3</scene>, resulting in a divergence of 8 angstroms from S1P<sub>1</sub> <ref name="regpeps">PMID: 26091040</ref>. This narrowing of the gap between TMI and TMVII blocks membrane ligand access, while the greater distance between ECL3 and the other extracellular loops promotes extracellular access. Additionally, ECL0 is helical in S1P<sub>1</sub>, but lacks secondary structure in LPA<sub>1</sub>. This increased flexibility that results further promotes favorable access from the extracellular space <ref name="regpeps">PMID: 26091040</ref>.<br />
<br />
<br />
<br />
=== Endocannabinoid Receptor 1 ===<br />
LPA<sub>1</sub> also is closely related to the [http://www.nature.com/ijo/journal/v30/n1s/full/0803272a.html cannabinoid receptor]. This close relation gives CB<sub>1</sub> ([[Cannabinoid Receptor 1]]) the ability to bind to analogs of LPA and vice versa, which opens the possibility of metabolic crosstalk between the two signaling systems. This connection is made possible through ligand phosphorylation and dephosphorylation <ref name="regpeps">PMID: 26091040</ref>. Specifically, complementary access to the LPA<sub>1</sub> binding pocket can be achieved by phosphorylated CB<sub>1</sub> ligand analogs, while complementary access to the CB<sub>1</sub> binding site requires dephosphorylation of LPA<sub>1</sub> ligand analogs. In both cases, a ligand could serve as a primary [https://en.wikipedia.org/wiki/Selective_receptor_modulator receptor modulator] and a simultaneous [https://en.wikipedia.org/wiki/Prodrug prodrug] for a different receptor <ref name="regpeps">PMID: 26091040</ref>.<br />
<br />
<scene name='72/721543/Asp129_and_trp210/2'>Residues Asp129 and Trp210</scene> located within the hydrophobic binding pocket of LPA<sub>1</sub> may share responsibility for the preference for long unsaturated acyl chains. These residues are also interesting in regard to GPCR phylogenic evolution (reference). Trp210 specifically only occurs in this position in 1% of all class A GPCR receptors and is unique to lysophospholipid and cannabinoid receptors. <ref name = 'Van Durme'>Van Durme, J., Horn, F., Costagliola, S., Vriend, G., and Vassart, G. “GRIS: glycoprotein-hormone receptor information system.” Mol. (2006) Endocrinol. 20, 2247-2255' </ref>.<br />
<br />
A model for lipid agonist binding generated through molecular modeling was used to dock two of the cannabinoid receptor CB<sub>1</sub>'s most abundant endogenous ligands into the LPA<sub>1</sub> binding pocket <ref name="regpeps">PMID: 26091040</ref>. Rotameric shifts of Trp210 and Trp271 leading to expansion of the binding pocket and the exposure of the π clouds of their indole rings provided favorable interactions with the double bonds of the phosphorylated cannabinoid ligands. This favorable binding provides evidence that the hydrophobic binding pockets of LPA<sub>1</sub> and CB<sub>1</sub> are able to favorably bind the same poly-unsaturated acyl chains with metabolically interconvertible head groups <ref name="regpeps">PMID: 26091040</ref>.<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Chandler Mitchellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1172&diff=2585021Sandbox Reserved 11722016-03-30T05:31:25Z<p>Chandler Mitchell: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Central_Metabolism}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Lysophosphatidic Acid Receptor 1==<br />
<StructureSection load='4z34' size='340' side='right' caption='Cartoon representation of the LPA1 protein and its antagonist, ON7, colored in white. ([https://en.wikipedia.org/wiki/Protein_Data_Bank PDB] code [http://www.rcsb.org/pdb/explore/explore.do?structureId=4z34 4Z34]) ' scene='72/721543/Overallrainbow/1'><br />
<br />
<br />
== Introduction ==<br />
Lysophosphatidic Acid Receptor 1 (commonly referred to as LPA<sub>1</sub>) is a [[G protein-coupled receptor]] and one of 6 different LPA receptors (LPA<sub>1</sub>-LPA<sub>6</sub>) that bind the phospholipid derivative [https://en.wikipedia.org/wiki/Lysophosphatidic_acid lysophosphatidic acid (LPA)], a signaling molecule that acts as a potent [https://en.wikipedia.org/wiki/Mitogen mitogen] upon binding to one of its six receptors.<ref name="regpeps">PMID: 26091040</ref>, ----------- LPA<sub>1</sub> is part of the larger [http://jb.oxfordjournals.org/content/131/6/767 EDG receptor family] which includes the more widely known sphingosine 1-phopshate receptors.<br />
== Structure ==<br />
[[Image:ABP.png|250 px|left|thumb|Electrostatic illustration of the amphipathic binding pocket of the LPA<sub>1</sub> receptor.]]<br />
The LPA<sub>1</sub> receptor protein is composed of 364 amino acids with a mass of approximately 41 kDa. Just as other G-protein coupled receptors, LPA<sub>1</sub> contains seven [http://kinemage.biochem.duke.edu/teaching/anatax/html/anatax.2a.html alpha helices] which make up the seven transmembrane spanning domains with three intracellular loops and three extracellular loops. The amino terminus of this protein is located on the extracellular side of the membrane, while the carboxyl terminus is located on the intracellular side of the membrane.<ref name = 'Hernández-Méndez'>Hernández-Méndez, Aurelio, Rocío Alcántara-Hernández, and J. Adolfo García-Sáinz. "Lysophosphatidic Acid LPA1-3 Receptors: Signaling, Regulation and in Silico Analysis of Their Putative Phosphorylation Sites." Receptors & Clinical Investigation Receptor Clin Invest 1.3 (2014). Web. 15 Feb. 2016.' </ref>. Within these helices is an amphipathic binding pocket which stabilizes the binding of its ligand, LPA.<br />
=== Key Ligand Interactions ===<br />
[[Image:ON7.png|250 px|right|thumb|Overall structure of the LPA<sub>1</sub> receptor in tan interacting with its antagonist, ON7, shown in green and red sticks.]]<br />
Three separate interactions with an antagonist of LPA<sub>1</sub>, ON7, help demonstrate the key interactions that stabilize the binding of the LPA phospholipid to this receptor. At the polar region of the binding pocket, the majority of this region is stabilized by <scene name='72/721543/Arg124gln125/1'>Arg124 and Gln125</scene> forming ionic and polar interactions with the carboxylic acid and the hydroxyl group of ON7.<ref name="regpeps">PMID: 26091040</ref> In addition, interplay between <scene name='72/721543/Lys39_and_glu293/4'>Glu293 and Lys39</scene> causes another stabilizing component of the ON7 antagonist. Glu293 forms polar interactions with Lys39, positioning it in close proximity to to the carboxylic acid of ON7, which then interactions with Lys39 via ionic bonding.<ref name="regpeps">PMID: 26091040</ref> While Lys39 is highly conserved among all six LPA receptors, a His40 residue is present that is specific to the LPA<sub>1</sub> receptor. <scene name='72/721543/His40/1'>His40</scene> forms both ionic and polar interactions with the carboxylic acid of ON7. The protonation of this residue has been found to greatly affect the binding affinity of LPA, and is an important link to tumor growth and survival in acidic environments.<ref name="regpeps">PMID: 26091040</ref><br />
<br />
<br />
== Function ==<br />
The LPA<sub>1</sub> receptor is present in nearly all cells and tissues throughout the body, and deletion of the LPA<sub>1</sub> receptor has been found to have physiological effects on every organ system, indicating its wide range of functions. Specifically, this receptor has been found to initiate downstream signaling cascades with three G<sub>α</sub> proteins: G<sub>i/o</sub>, G<sub>q/11</sub>, and G<sub>12/13</sub>. These G<sub>α</sub> proteins begin signaling cascades with molecules such as [https://en.wikipedia.org/wiki/Phospholipase_C phospholipase C] and [[MAPK]] that signal for cell proliferation, survival, and migration. <ref name = 'Yung'>Yung, Y. C., N. C. Stoddard, and J. Chun. "LPA Receptor Signaling: Pharmacology, Physiology, and Pathophysiology." The Journal of Lipid Research 55.7 (2014): 1192-214. Web. 17 Feb. 2016.' </ref>.Despite this receptor being expressed throughout the body, LPA<sub>1</sub> has been found to be expressed highly in neural tissue, aiding in several different neurodevelopmental processes including growth and folding of the [https://www.dartmouth.edu/~rswenson/NeuroSci/chapter_11.html cerebral cortex] and the growth, survival, and migration of neural [https://en.wikipedia.org/wiki/Progenitor_cell progenitor cells] through its different [https://en.wikipedia.org/wiki/G_protein link G-protein] regulated pathways.<ref name = 'Chun'>Chun, J., Hla, T., Spiegel, S., and Moolenaar, W.H. “Lysophospholipid Receptors: Signaling and Biochemistry.” John Wiley & Sons, Inc. (2013) pp.i-xviii. 5 Feb. 2016.' </ref>. Finally, LPA1 receptors expressed in neural tissue aid in Schwann cell migration and myelination through a signaling pathway with the [https://en.wikipedia.org/wiki/RAC1 Rac1] G-protein.<ref name="number5">PMID: 24115248</ref>.<br />
<br />
<br />
== Disease Relevance ==<br />
Because LPA<sub>1</sub> is expressed in so many tissues throughout the body, it has been linked to the symptoms and progression of several different diseases and disorders. For example, due to LPA<sub>1</sub>'s role in pain signaling, overexpression of this protein can cause both [https://en.wikipedia.org/wiki/Allodynia allodynia] or [https://en.wikipedia.org/wiki/Hyperalgesia hyperalgesia], common symptoms of multiple sclerosis or strokes. In addition, since LPA<sub>1</sub> helps in the myelination of Schwann cells, mutation of the receptor can also lead to a decrease in [https://en.wikipedia.org/wiki/Prepulse_inhibition prepulse inhibition], a general sign of schizophrenia.<ref name="number6">PMID: 20331961</ref>.Lastly, because of the mitogen signaling activity of LPA<sub>1</sub>, abnormal expression or mutation of this receptor has been linked to tumor growth, survival, and migration in both liver and lung tumors. As recently discussed, the His40 on LPA<sub>1</sub>, when protonated, increased LPA binding affinity is increase by up to 1kcal/mol. Because of this, in an acidic environment that is typically produced by [https://en.wikipedia.org/wiki/Tumor_hypoxia hypoxic tumors] creating lactic acid, LPA<sub>1</sub> activity is increased, allowing these tumors to continue to proliferate, migrate, and survive.<ref name="number7">PMID: 24367336</ref>. In contrast, the LPA<sub>1</sub> receptor has also been found to induce protective functions in the presence of a particular illness. For example, in patients with heart disease, LPA<sub>1</sub> has been found to communicate with [[PI3K]], [https://en.wikipedia.org/wiki/Protein_kinase_B PKB], and [[ERK]] to create a hypertrophic response in the heart in order to offset reduced heart contractions.<br />
<br />
== Receptor Comparison ==<br />
<br />
=== Sphingosine 1-Phosphate Receptor ===<br />
LPA<sub>1</sub> belongs to the EDG (endothelial differentiation gene) family of [https://en.wikipedia.org/wiki/Lysophospholipid_receptor lysophospholipid receptors]. This family also includes the [https://en.wikipedia.org/wiki/S1PR1 sphingosine 1-phosphate receptor 1] (S1P<sub>1</sub>), which has many structural similarities to LPA<sub>1</sub>. In fact, the transmembrane regions share a sequence identity of 41%. A defining difference between these two receptors is their mode of ligand access to the binding site. Where as the hydrophobic [https://en.wikipedia.org/wiki/Sphingosine-1-phosphate S1P ligand] enters S1P<sub>1</sub> via the membrane, LPA<sub>1</sub> has an extracellular opening that allows LPA access from the extracellular space <ref name="regpeps">PMID: 26091040</ref>. Structural evidence for this altered ligand pathway include global changes in the positioning of the extracellular loops (ECL) and transmembrane helices (TM). Specifically, this includes slight divergence of <scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene>, which is positioned 3 angstroms closer to TMVII compared to S1P<sub>1</sub>, and a repositioning of <scene name='72/721543/Ecl_regions/1'>ECL3</scene>, resulting in a divergence of 8 angstroms from S1P<sub>1</sub> <ref name="regpeps">PMID: 26091040</ref>. This narrowing of the gap between TMI and TMVII blocks membrane ligand access, while the greater distance between ECL3 and the other extracellular loops promotes extracellular access. Additionally, ECL0 is helical in S1P<sub>1</sub>, but lacks secondary structure in LPA<sub>1</sub>. This increased flexibility that results further promotes favorable access from the extracellular space <ref name="regpeps">PMID: 26091040</ref>.<br />
<br />
<br />
<br />
=== Endocannabinoid Receptor 1 ===<br />
LPA<sub>1</sub> also is closely related to the [http://www.nature.com/ijo/journal/v30/n1s/full/0803272a.html cannabinoid receptor]. This close relation gives CB<sub>1</sub> ([[Cannabinoid Receptor 1]]) the ability to bind to analogs of LPA and vice versa, which opens the possibility of metabolic crosstalk between the two signaling systems. This connection is made possible through ligand phosphorylation and dephosphorylation <ref name="regpeps">PMID: 26091040</ref>. Specifically, complementary access to the LPA<sub>1</sub> binding pocket can be achieved by phosphorylated CB<sub>1</sub> ligand analogs, while complementary access to the CB<sub>1</sub> binding site requires dephosphorylation of LPA<sub>1</sub> ligand analogs. In both cases, a ligand could serve as a primary [https://en.wikipedia.org/wiki/Selective_receptor_modulator receptor modulator] and a simultaneous [https://en.wikipedia.org/wiki/Prodrug prodrug] for a different receptor <ref name="regpeps">PMID: 26091040</ref>.<br />
<br />
<scene name='72/721543/Asp129_and_trp210/2'>Residues Asp129 and Trp210</scene> located within the hydrophobic binding pocket of LPA<sub>1</sub> may share responsibility for the preference for long unsaturated acyl chains. These residues are also interesting in regard to GPCR phylogenic evolution (reference). Trp210 specifically only occurs in this position in 1% of all class A GPCR receptors and is unique to lysophospholipid and cannabinoid receptors.<br />
<br />
A model for lipid agonist binding generated through molecular modeling was used to dock two of the cannabinoid receptor CB<sub>1</sub>'s most abundant endogenous ligands into the LPA<sub>1</sub> binding pocket <ref name="regpeps">PMID: 26091040</ref>. Rotameric shifts of Trp210 and Trp271 leading to expansion of the binding pocket and the exposure of the π clouds of their indole rings provided favorable interactions with the double bonds of the phosphorylated cannabinoid ligands. This favorable binding provides evidence that the hydrophobic binding pockets of LPA<sub>1</sub> and CB<sub>1</sub> are able to favorably bind the same poly-unsaturated acyl chains with metabolically interconvertible head groups <ref name="regpeps">PMID: 26091040</ref>.<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Chandler Mitchellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1172&diff=2585020Sandbox Reserved 11722016-03-30T05:26:31Z<p>Chandler Mitchell: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Central_Metabolism}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Lysophosphatidic Acid Receptor 1==<br />
<StructureSection load='4z34' size='340' side='right' caption='Cartoon representation of the LPA1 protein and its antagonist, ON7, colored in white. ([https://en.wikipedia.org/wiki/Protein_Data_Bank PDB] code [http://www.rcsb.org/pdb/explore/explore.do?structureId=4z34 4Z34]) ' scene='72/721543/Overallrainbow/1'><br />
<br />
<br />
== Introduction ==<br />
Lysophosphatidic Acid Receptor 1 (commonly referred to as LPA<sub>1</sub>) is a [[G protein-coupled receptor]] and one of 6 different LPA receptors (LPA<sub>1</sub>-LPA<sub>6</sub>) that bind the phospholipid derivative [https://en.wikipedia.org/wiki/Lysophosphatidic_acid lysophosphatidic acid (LPA)], a signaling molecule that acts as a potent [https://en.wikipedia.org/wiki/Mitogen mitogen] upon binding to one of its six receptors.<ref name="regpeps">PMID: 26091040</ref>, ----------- LPA<sub>1</sub> is part of the larger EDG receptor family(link) which includes the more widely known sphingosine 1-phopshate receptors.<br />
== Structure ==<br />
[[Image:ABP.png|250 px|left|thumb|Electrostatic illustration of the amphipathic binding pocket of the LPA<sub>1</sub> receptor.]]<br />
The LPA<sub>1</sub> receptor protein is composed of 364 amino acids with a mass of approximately 41 kDa. Just as other G-protein coupled receptors, LPA<sub>1</sub> contains seven [http://kinemage.biochem.duke.edu/teaching/anatax/html/anatax.2a.html alpha helices] which make up the seven transmembrane spanning domains with three intracellular loops and three extracellular loops. The amino terminus of this protein is located on the extracellular side of the membrane, while the carboxyl terminus is located on the intracellular side of the membrane.<ref name = 'Hernández-Méndez'>Hernández-Méndez, Aurelio, Rocío Alcántara-Hernández, and J. Adolfo García-Sáinz. "Lysophosphatidic Acid LPA1-3 Receptors: Signaling, Regulation and in Silico Analysis of Their Putative Phosphorylation Sites." Receptors & Clinical Investigation Receptor Clin Invest 1.3 (2014). Web. 15 Feb. 2016.' </ref>. Within these helices is an amphipathic binding pocket which stabilizes the binding of its ligand, LPA.<br />
=== Key Ligand Interactions ===<br />
[[Image:ON7.png|250 px|right|thumb|Overall structure of the LPA<sub>1</sub> receptor in tan interacting with its antagonist, ON7, shown in green and red sticks.]]<br />
Three separate interactions with an antagonist of LPA<sub>1</sub>, ON7, help demonstrate the key interactions that stabilize the binding of the LPA phospholipid to this receptor. At the polar region of the binding pocket, the majority of this region is stabilized by <scene name='72/721543/Arg124gln125/1'>Arg124 and Gln125</scene> forming ionic and polar interactions with the carboxylic acid and the hydroxyl group of ON7.<ref name="regpeps">PMID: 26091040</ref> In addition, interplay between <scene name='72/721543/Lys39_and_glu293/4'>Glu293 and Lys39</scene> causes another stabilizing component of the ON7 antagonist. Glu293 forms polar interactions with Lys39, positioning it in close proximity to to the carboxylic acid of ON7, which then interactions with Lys39 via ionic bonding.<ref name="regpeps">PMID: 26091040</ref> While Lys39 is highly conserved among all six LPA receptors, a His40 residue is present that is specific to the LPA<sub>1</sub> receptor. <scene name='72/721543/His40/1'>His40</scene> forms both ionic and polar interactions with the carboxylic acid of ON7. The protonation of this residue has been found to greatly affect the binding affinity of LPA, and is an important link to tumor growth and survival in acidic environments.<ref name="regpeps">PMID: 26091040</ref><br />
<br />
<br />
== Function ==<br />
The LPA<sub>1</sub> receptor is present in nearly all cells and tissues throughout the body, and deletion of the LPA<sub>1</sub> receptor has been found to have physiological effects on every organ system, indicating its wide range of functions. Specifically, this receptor has been found to initiate downstream signaling cascades with three G<sub>α</sub> proteins: G<sub>i/o</sub>, G<sub>q/11</sub>, and G<sub>12/13</sub>. These G<sub>α</sub> proteins begin signaling cascades with molecules such as [https://en.wikipedia.org/wiki/Phospholipase_C phospholipase C] and [[MAPK]] that signal for cell proliferation, survival, and migration. <ref name = 'Yung'>Yung, Y. C., N. C. Stoddard, and J. Chun. "LPA Receptor Signaling: Pharmacology, Physiology, and Pathophysiology." The Journal of Lipid Research 55.7 (2014): 1192-214. Web. 17 Feb. 2016.' </ref>.Despite this receptor being expressed throughout the body, LPA<sub>1</sub> has been found to be expressed highly in neural tissue, aiding in several different neurodevelopmental processes including growth and folding of the [https://www.dartmouth.edu/~rswenson/NeuroSci/chapter_11.html cerebral cortex] and the growth, survival, and migration of neural [https://en.wikipedia.org/wiki/Progenitor_cell progenitor cells] through its different [https://en.wikipedia.org/wiki/G_protein link G-protein] regulated pathways.<ref name = 'Chun'>Chun, J., Hla, T., Spiegel, S., and Moolenaar, W.H. “Lysophospholipid Receptors: Signaling and Biochemistry.” John Wiley & Sons, Inc. (2013) pp.i-xviii. 5 Feb. 2016.' </ref>. Finally, LPA1 receptors expressed in neural tissue aid in Schwann cell migration and myelination through a signaling pathway with the [https://en.wikipedia.org/wiki/RAC1 Rac1] G-protein.<ref name="number5">PMID: 24115248</ref>.<br />
<br />
<br />
== Disease Relevance ==<br />
Because LPA<sub>1</sub> is expressed in so many tissues throughout the body, it has been linked to the symptoms and progression of several different diseases and disorders. For example, due to LPA<sub>1</sub>'s role in pain signaling, overexpression of this protein can cause both [https://en.wikipedia.org/wiki/Allodynia allodynia] or [https://en.wikipedia.org/wiki/Hyperalgesia hyperalgesia], common symptoms of multiple sclerosis or strokes. In addition, since LPA<sub>1</sub> helps in the myelination of Schwann cells, mutation of the receptor can also lead to a decrease in [https://en.wikipedia.org/wiki/Prepulse_inhibition prepulse inhibition], a general sign of schizophrenia.<ref name="number6">PMID: 20331961</ref>.Lastly, because of the mitogen signaling activity of LPA<sub>1</sub>, abnormal expression or mutation of this receptor has been linked to tumor growth, survival, and migration in both liver and lung tumors. As recently discussed, the His40 on LPA<sub>1</sub>, when protonated, increased LPA binding affinity is increase by up to 1kcal/mol. Because of this, in an acidic environment that is typically produced by [https://en.wikipedia.org/wiki/Tumor_hypoxia hypoxic tumors] creating lactic acid, LPA<sub>1</sub> activity is increased, allowing these tumors to continue to proliferate, migrate, and survive.<ref name="number7">PMID: 24367336</ref>. In contrast, the LPA<sub>1</sub> receptor has also been found to induce protective functions in the presence of a particular illness. For example, in patients with heart disease, LPA<sub>1</sub> has been found to communicate with [[PI3K]], [https://en.wikipedia.org/wiki/Protein_kinase_B PKB], and [[ERK]] to create a hypertrophic response in the heart in order to offset reduced heart contractions.<br />
<br />
== Receptor Comparison ==<br />
<br />
=== Sphingosine 1-Phosphate Receptor ===<br />
LPA<sub>1</sub> belongs to the EDG (endothelial differentiation gene) family of [https://en.wikipedia.org/wiki/Lysophospholipid_receptor lysophospholipid receptors]. This family also includes the [https://en.wikipedia.org/wiki/S1PR1 sphingosine 1-phosphate receptor 1] (S1P<sub>1</sub>), which has many structural similarities to LPA<sub>1</sub>. In fact, the transmembrane regions share a sequence identity of 41%. A defining difference between these two receptors is their mode of ligand access to the binding site. Where as the hydrophobic [https://en.wikipedia.org/wiki/Sphingosine-1-phosphate S1P ligand] enters S1P<sub>1</sub> via the membrane, LPA<sub>1</sub> has an extracellular opening that allows LPA access from the extracellular space <ref name="regpeps">PMID: 26091040</ref>. Structural evidence for this altered ligand pathway include global changes in the positioning of the extracellular loops (ECL) and transmembrane helices (TM). Specifically, this includes slight divergence of <scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene>, which is positioned 3 angstroms closer to TMVII compared to S1P<sub>1</sub>, and a repositioning of <scene name='72/721543/Ecl_regions/1'>ECL3</scene>, resulting in a divergence of 8 angstroms from S1P<sub>1</sub> <ref name="regpeps">PMID: 26091040</ref>. This narrowing of the gap between TMI and TMVII blocks membrane ligand access, while the greater distance between ECL3 and the other extracellular loops promotes extracellular access. Additionally, ECL0 is helical in S1P<sub>1</sub>, but lacks secondary structure in LPA<sub>1</sub>. This increased flexibility that results further promotes favorable access from the extracellular space <ref name="regpeps">PMID: 26091040</ref>.<br />
<br />
<br />
<br />
=== Endocannabinoid Receptor 1 ===<br />
LPA<sub>1</sub> also is closely related to the [http://www.nature.com/ijo/journal/v30/n1s/full/0803272a.html cannabinoid receptor]. This close relation gives CB<sub>1</sub> ([[Cannabinoid Receptor 1]]) the ability to bind to analogs of LPA and vice versa, which opens the possibility of metabolic crosstalk between the two signaling systems. This connection is made possible through ligand phosphorylation and dephosphorylation <ref name="regpeps">PMID: 26091040</ref>. Specifically, complementary access to the LPA<sub>1</sub> binding pocket can be achieved by phosphorylated CB<sub>1</sub> ligand analogs, while complementary access to the CB<sub>1</sub> binding site requires dephosphorylation of LPA<sub>1</sub> ligand analogs. In both cases, a ligand could serve as a primary [https://en.wikipedia.org/wiki/Selective_receptor_modulator receptor modulator] and a simultaneous [https://en.wikipedia.org/wiki/Prodrug prodrug] for a different receptor <ref name="regpeps">PMID: 26091040</ref>.<br />
<br />
<scene name='72/721543/Asp129_and_trp210/2'>Residues Asp129 and Trp210</scene> located within the hydrophobic binding pocket of LPA<sub>1</sub> may share responsibility for the preference for long unsaturated acyl chains. These residues are also interesting in regard to GPCR phylogenic evolution (reference). Trp210 specifically only occurs in this position in 1% of all class A GPCR receptors and is unique to lysophospholipid and cannabinoid receptors.<br />
<br />
A model for lipid agonist binding generated through molecular modeling was used to dock two of the cannabinoid receptor CB<sub>1</sub>'s most abundant endogenous ligands into the LPA<sub>1</sub> binding pocket <ref name="regpeps">PMID: 26091040</ref>. Rotameric shifts of Trp210 and Trp271 leading to expansion of the binding pocket and the exposure of the π clouds of their indole rings provided favorable interactions with the double bonds of the phosphorylated cannabinoid ligands. This favorable binding provides evidence that the hydrophobic binding pockets of LPA<sub>1</sub> and CB<sub>1</sub> are able to favorably bind the same poly-unsaturated acyl chains with metabolically interconvertible head groups <ref name="regpeps">PMID: 26091040</ref>.<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Chandler Mitchellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1172&diff=2585019Sandbox Reserved 11722016-03-30T05:19:30Z<p>Chandler Mitchell: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Central_Metabolism}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Lysophosphatidic Acid Receptor 1==<br />
<StructureSection load='4z34' size='340' side='right' caption='Cartoon representation of the LPA1 protein and its antagonist, ON7, colored in white. ([https://en.wikipedia.org/wiki/Protein_Data_Bank PDB] code [http://www.rcsb.org/pdb/explore/explore.do?structureId=4z34 4Z34]) ' scene='72/721543/Overallrainbow/1'><br />
<br />
<br />
== Introduction ==<br />
Lysophosphatidic Acid Receptor 1 (commonly referred to as LPA<sub>1</sub>) is a [[G protein-coupled receptor]] and one of 6 different LPA receptors (LPA<sub>1</sub>-LPA<sub>6</sub>) that bind the phospholipid derivative [https://en.wikipedia.org/wiki/Lysophosphatidic_acid lysophosphatidic acid (LPA)], a signaling molecule that acts as a potent [https://en.wikipedia.org/wiki/Mitogen mitogen] upon binding to one of its six receptors.<ref name="regpeps">PMID: 26091040</ref>, ----------- LPA<sub>1</sub> is part of the larger EDG receptor family(link) which includes the more widely known sphingosine 1-phopshate receptors.<br />
== Structure ==<br />
[[Image:ABP.png|250 px|left|thumb|Electrostatic illustration of the amphipathic binding pocket of the LPA<sub>1</sub> receptor.]]<br />
The LPA<sub>1</sub> receptor protein is composed of 364 amino acids with a mass of approximately 41 kDa. Just as other G-protein coupled receptors, LPA<sub>1</sub> contains seven [http://kinemage.biochem.duke.edu/teaching/anatax/html/anatax.2a.html alpha helices] which make up the seven transmembrane spanning domains with three intracellular loops and three extracellular loops. The amino terminus of this protein is located on the extracellular side of the membrane, while the carboxyl terminus is located on the intracellular side of the membrane.<ref name = 'Hernández-Méndez'>Hernández-Méndez, Aurelio, Rocío Alcántara-Hernández, and J. Adolfo García-Sáinz. "Lysophosphatidic Acid LPA1-3 Receptors: Signaling, Regulation and in Silico Analysis of Their Putative Phosphorylation Sites." Receptors & Clinical Investigation Receptor Clin Invest 1.3 (2014). Web. 15 Feb. 2016.' </ref>. Within these helices is an amphipathic binding pocket which stabilizes the binding of its ligand, LPA.<br />
=== Key Ligand Interactions ===<br />
[[Image:ON7.png|250 px|right|thumb|Overall structure of the LPA<sub>1</sub> receptor in tan interacting with its antagonist, ON7, shown in green and red sticks.]]<br />
Three separate interactions with an antagonist of LPA<sub>1</sub>, ON7, help demonstrate the key interactions that stabilize the binding of the LPA phospholipid to this receptor. At the polar region of the binding pocket, the majority of this region is stabilized by <scene name='72/721543/Arg124gln125/1'>Arg124 and Gln125</scene> forming ionic and polar interactions with the carboxylic acid and the hydroxyl group of ON7.<ref name="regpeps">PMID: 26091040</ref> In addition, interplay between <scene name='72/721543/Lys39_and_glu293/4'>Glu293 and Lys39</scene> causes another stabilizing component of the ON7 antagonist. Glu293 forms polar interactions with Lys39, positioning it in close proximity to to the carboxylic acid of ON7, which then interactions with Lys39 via ionic bonding.<ref name="regpeps">PMID: 26091040</ref> While Lys39 is highly conserved among all six LPA receptors, a His40 residue is present that is specific to the LPA<sub>1</sub> receptor. <scene name='72/721543/His40/1'>His40</scene> forms both ionic and polar interactions with the carboxylic acid of ON7. The protonation of this residue has been found to greatly affect the binding affinity of LPA, and is an important link to tumor growth and survival in acidic environments.<ref name="regpeps">PMID: 26091040</ref><br />
<br />
<br />
== Function ==<br />
The LPA<sub>1</sub> receptor is present in nearly all cells and tissues throughout the body, and deletion of the LPA<sub>1</sub> receptor has been found to have physiological effects on every organ system, indicating its wide range of functions. Specifically, this receptor has been found to initiate downstream signaling cascades with three G<sub>α</sub> proteins: G<sub>i/o</sub>, G<sub>q/11</sub>, and G<sub>12/13</sub>. These G<sub>α</sub> proteins begin signaling cascades with molecules such as [https://en.wikipedia.org/wiki/Phospholipase_C phospholipase C] and [[MAPK]] that signal for cell proliferation, survival, and migration. <ref name = 'Yung'>Yung, Y. C., N. C. Stoddard, and J. Chun. "LPA Receptor Signaling: Pharmacology, Physiology, and Pathophysiology." The Journal of Lipid Research 55.7 (2014): 1192-214. Web. 17 Feb. 2016.' </ref>.Despite this receptor being expressed throughout the body, LPA<sub>1</sub> has been found to be expressed highly in neural tissue, aiding in several different neurodevelopmental processes including growth and folding of the [https://www.dartmouth.edu/~rswenson/NeuroSci/chapter_11.html cerebral cortex] and the growth, survival, and migration of neural [https://en.wikipedia.org/wiki/Progenitor_cell progenitor cells] through its different [https://en.wikipedia.org/wiki/G_protein link G-protein] regulated pathways.<ref name = 'Chun'>Chun, J., Hla, T., Spiegel, S., and Moolenaar, W.H. “Lysophospholipid Receptors: Signaling and Biochemistry.” John Wiley & Sons, Inc. (2013) pp.i-xviii. 5 Feb. 2016.' </ref>. Finally, LPA1 receptors expressed in neural tissue aid in Schwann cell migration and myelination through a signaling pathway with the [https://en.wikipedia.org/wiki/RAC1 Rac1] G-protein.<ref name="number5">PMID: 24115248</ref>.<br />
<br />
<br />
== Disease Relevance ==<br />
Because LPA<sub>1</sub> is expressed in so many tissues throughout the body, it has been linked to the symptoms and progression of several different diseases and disorders. For example, due to LPA<sub>1</sub>'s role in pain signaling, overexpression of this protein can cause both [https://en.wikipedia.org/wiki/Allodynia allodynia] or [https://en.wikipedia.org/wiki/Hyperalgesia hyperalgesia], common symptoms of multiple sclerosis or strokes. In addition, since LPA<sub>1</sub> helps in the myelination of Schwann cells, mutation of the receptor can also lead to a decrease in [https://en.wikipedia.org/wiki/Prepulse_inhibition prepulse inhibition], a general sign of schizophrenia.<ref name="number6">PMID: 20331961</ref>.Lastly, because of the mitogen signaling activity of LPA<sub>1</sub>, abnormal expression or mutation of this receptor has been linked to tumor growth, survival, and migration in both liver and lung tumors. As recently discussed, the His40 on LPA<sub>1</sub>, when protonated, increased LPA binding affinity is increase by up to 1kcal/mol. Because of this, in an acidic environment that is typically produced by [https://en.wikipedia.org/wiki/Tumor_hypoxia hypoxic tumors] creating lactic acid, LPA<sub>1</sub> activity is increased, allowing these tumors to continue to proliferate, migrate, and survive.<ref name="number7">PMID: 24367336</ref>. In contrast, the LPA<sub>1</sub> receptor has also been found to induce protective functions in the presence of a particular illness. For example, in patients with heart disease, LPA<sub>1</sub> has been found to communicate with [[PI3K]], [https://en.wikipedia.org/wiki/Protein_kinase_B PKB], and [[ERK]] to create a hypertrophic response in the heart in order to offset reduced heart contractions.<br />
<br />
== Receptor Comparison ==<br />
<br />
=== Sphingosine 1-Phosphate Receptor ===<br />
LPA<sub>1</sub> belongs to the EDG (endothelial differentiation gene) family of [https://en.wikipedia.org/wiki/Lysophospholipid_receptor lysophospholipid receptors]. This family also includes the [https://en.wikipedia.org/wiki/S1PR1 sphingosine 1-phosphate receptor 1] (S1P<sub>1</sub>), which has many structural similarities to LPA<sub>1</sub>. In fact, the transmembrane regions share a sequence identity of 41%. A defining difference between these two receptors is their mode of ligand access to the binding site. Where as the hydrophobic [https://en.wikipedia.org/wiki/Sphingosine-1-phosphate S1P ligand] enters S1P<sub>1</sub> via the membrane, LPA<sub>1</sub> has an extracellular opening that allows LPA access from the extracellular space <ref name="regpeps">PMID: 26091040</ref>. Structural evidence for this altered ligand pathway include global changes in the positioning of the extracellular loops (ECL) and transmembrane helices (TM). Specifically, this includes slight divergence of <scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene>, which is positioned 3 angstroms closer to TMVII compared to S1P<sub>1</sub>, and a repositioning of <scene name='72/721543/Ecl_regions/1'>ECL3</scene>, resulting in a divergence of 8 angstroms from S1P<sub>1</sub> <ref name="regpeps">PMID: 26091040</ref>. This narrowing of the gap between TMI and TMVII blocks membrane ligand access, while the greater distance between ECL3 and the other extracellular loops promotes extracellular access. Additionally, ECL0 is helical in S1P<sub>1</sub>, but lacks secondary structure in LPA<sub>1</sub>. This increased flexibility that results further promotes favorable access from the extracellular space <ref name="regpeps">PMID: 26091040</ref>.<br />
<br />
<br />
<br />
=== Endocannabinoid Receptor 1 ===<br />
LPA<sub>1</sub> also is closely related to the [http://www.nature.com/ijo/journal/v30/n1s/full/0803272a.html cannabinoid receptor]. This close relation gives CB<sub>1</sub> ([[Cannabinoid Receptor 1]]) the ability to bind to analogs of LPA and vice versa, which opens the possibility of metabolic crosstalk between the two signaling systems. This connection is made possible through ligand phosphorylation and dephosphorylation. Specifically, complementary access to the LPA<sub>1</sub> binding pocket can be achieved by phosphorylated CB<sub>1</sub> ligand analogs, while complementary access to the CB<sub>1</sub> binding site requires dephosphorylation of LPA<sub>1</sub> ligand analogs. In both cases, a ligand could serve as a primary [https://en.wikipedia.org/wiki/Selective_receptor_modulator receptor modulator] and a simultaneous [https://en.wikipedia.org/wiki/Prodrug prodrug] for a different receptor.<br />
<br />
<scene name='72/721543/Asp129_and_trp210/2'>Residues Asp129 and Trp210</scene> located within the hydrophobic binding pocket of LPA<sub>1</sub> may share responsibility for the preference for long unsaturated acyl chains. These residues are also interesting in regard to GPCR phylogenic evolution (reference). Trp210 specifically only occurs in this position in 1% of all class A GPCR receptors and is unique to lysophospholipid and cannabinoid receptors.<br />
<br />
A model for lipid agonist binding generated through molecular modeling was used to dock two of the cannabinoid receptor CB<sub>1</sub>'s most abundant endogenous ligands into the LPA<sub>1</sub> binding pocket. Rotameric shifts of Trp210 and Trp271 leading to expansion of the binding pocket and the exposure of the π clouds of their indole rings provided favorable interactions with the double bonds of the phosphorylated cannabinoid ligands. This favorable binding provides evidence that the hydrophobic binding pockets of LPA<sub>1</sub> and CB<sub>1</sub> are able to favorably bind the same poly-unsaturated acyl chains with metabolically interconvertible head groups.<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Chandler Mitchellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1172&diff=2585018Sandbox Reserved 11722016-03-30T05:18:55Z<p>Chandler Mitchell: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Central_Metabolism}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Lysophosphatidic Acid Receptor 1==<br />
<StructureSection load='4z34' size='340' side='right' caption='Cartoon representation of the LPA1 protein and its antagonist, ON7, colored in white. ([https://en.wikipedia.org/wiki/Protein_Data_Bank PDB] code [http://www.rcsb.org/pdb/explore/explore.do?structureId=4z34 4Z34]) ' scene='72/721543/Overallrainbow/1'><br />
<br />
<br />
== Introduction ==<br />
Lysophosphatidic Acid Receptor 1 (commonly referred to as LPA<sub>1</sub>) is a [[G protein-coupled receptor]] and one of 6 different LPA receptors (LPA<sub>1</sub>-LPA<sub>6</sub>) that bind the phospholipid derivative [https://en.wikipedia.org/wiki/Lysophosphatidic_acid lysophosphatidic acid (LPA)], a signaling molecule that acts as a potent [https://en.wikipedia.org/wiki/Mitogen mitogen] upon binding to one of its six receptors.<ref name="regpeps">PMID: 26091040</ref>, ----------- LPA<sub>1</sub> is part of the larger EDG receptor family(link) which includes the more widely known sphingosine 1-phopshate receptors.<br />
== Structure ==<br />
[[Image:ABP.png|250 px|left|thumb|Electrostatic illustration of the amphipathic binding pocket of the LPA<sub>1</sub> receptor.]]<br />
The LPA<sub>1</sub> receptor protein is composed of 364 amino acids with a mass of approximately 41 kDa. Just as other G-protein coupled receptors, LPA<sub>1</sub> contains seven [http://kinemage.biochem.duke.edu/teaching/anatax/html/anatax.2a.html alpha helices] which make up the seven transmembrane spanning domains with three intracellular loops and three extracellular loops. The amino terminus of this protein is located on the extracellular side of the membrane, while the carboxyl terminus is located on the intracellular side of the membrane.<ref name = 'Hernández-Méndez'>Hernández-Méndez, Aurelio, Rocío Alcántara-Hernández, and J. Adolfo García-Sáinz. "Lysophosphatidic Acid LPA1-3 Receptors: Signaling, Regulation and in Silico Analysis of Their Putative Phosphorylation Sites." Receptors & Clinical Investigation Receptor Clin Invest 1.3 (2014). Web. 15 Feb. 2016.' </ref>. Within these helices is an amphipathic binding pocket which stabilizes the binding of its ligand, LPA.<br />
=== Key Ligand Interactions ===<br />
[[Image:ON7.png|250 px|right|thumb|Overall structure of the LPA<sub>1</sub> receptor in tan interacting with its antagonist, ON7, shown in green and red sticks.]]<br />
Three separate interactions with an antagonist of LPA<sub>1</sub>, ON7, help demonstrate the key interactions that stabilize the binding of the LPA phospholipid to this receptor. At the polar region of the binding pocket, the majority of this region is stabilized by <scene name='72/721543/Arg124gln125/1'>Arg124 and Gln125</scene> forming ionic and polar interactions with the carboxylic acid and the hydroxyl group of ON7.<ref name="regpeps">PMID: 26091040</ref> In addition, interplay between <scene name='72/721543/Lys39_and_glu293/4'>Glu293 and Lys39</scene> causes another stabilizing component of the ON7 antagonist. Glu293 forms polar interactions with Lys39, positioning it in close proximity to to the carboxylic acid of ON7, which then interactions with Lys39 via ionic bonding.<ref name="regpeps">PMID: 26091040</ref> While Lys39 is highly conserved among all six LPA receptors, a His40 residue is present that is specific to the LPA<sub>1</sub> receptor. <scene name='72/721543/His40/1'>His40</scene> forms both ionic and polar interactions with the carboxylic acid of ON7. The protonation of this residue has been found to greatly affect the binding affinity of LPA, and is an important link to tumor growth and survival in acidic environments.<ref name="regpeps">PMID: 26091040</ref><br />
<br />
<br />
== Function ==<br />
The LPA<sub>1</sub> receptor is present in nearly all cells and tissues throughout the body, and deletion of the LPA<sub>1</sub> receptor has been found to have physiological effects on every organ system, indicating its wide range of functions. Specifically, this receptor has been found to initiate downstream signaling cascades with three G<sub>α</sub> proteins: G<sub>i/o</sub>, G<sub>q/11</sub>, and G<sub>12/13</sub>. These G<sub>α</sub> proteins begin signaling cascades with molecules such as [https://en.wikipedia.org/wiki/Phospholipase_C phospholipase C] and [[MAPK]] that signal for cell proliferation, survival, and migration. <ref name = 'Yung'>Yung, Y. C., N. C. Stoddard, and J. Chun. "LPA Receptor Signaling: Pharmacology, Physiology, and Pathophysiology." The Journal of Lipid Research 55.7 (2014): 1192-214. Web. 17 Feb. 2016.' </ref>.Despite this receptor being expressed throughout the body, LPA<sub>1</sub> has been found to be expressed highly in neural tissue, aiding in several different neurodevelopmental processes including growth and folding of the [https://www.dartmouth.edu/~rswenson/NeuroSci/chapter_11.html cerebral cortex] and the growth, survival, and migration of neural [https://en.wikipedia.org/wiki/Progenitor_cell progenitor cells] through its different [https://en.wikipedia.org/wiki/G_protein link G-protein] regulated pathways.<ref name = 'Chun'>Chun, J., Hla, T., Spiegel, S., and Moolenaar, W.H. “Lysophospholipid Receptors: Signaling and Biochemistry.” John Wiley & Sons, Inc. (2013) pp.i-xviii. 5 Feb. 2016.' </ref>. Finally, LPA1 receptors expressed in neural tissue aid in Schwann cell migration and myelination through a signaling pathway with the [https://en.wikipedia.org/wiki/RAC1 Rac1] G-protein.<ref name="number5">PMID: 24115248</ref>.<br />
<br />
<br />
== Disease Relevance ==<br />
Because LPA<sub>1</sub> is expressed in so many tissues throughout the body, it has been linked to the symptoms and progression of several different diseases and disorders. For example, due to LPA<sub>1</sub>'s role in pain signaling, overexpression of this protein can cause both [https://en.wikipedia.org/wiki/Allodynia allodynia] or [https://en.wikipedia.org/wiki/Hyperalgesia hyperalgesia], common symptoms of multiple sclerosis or strokes. In addition, since LPA<sub>1</sub> helps in the myelination of Schwann cells, mutation of the receptor can also lead to a decrease in [https://en.wikipedia.org/wiki/Prepulse_inhibition prepulse inhibition], a general sign of schizophrenia.<ref name="number6">PMID: 20331961</ref>.Lastly, because of the mitogen signaling activity of LPA<sub>1</sub>, abnormal expression or mutation of this receptor has been linked to tumor growth, survival, and migration in both liver and lung tumors. As recently discussed, the His40 on LPA<sub>1</sub>, when protonated, increased LPA binding affinity is increase by up to 1kcal/mol. Because of this, in an acidic environment that is typically produced by [https://en.wikipedia.org/wiki/Tumor_hypoxia hypoxic tumors] creating lactic acid, LPA<sub>1</sub> activity is increased, allowing these tumors to continue to proliferate, migrate, and survive.<ref name="number7">PMID: 24367336</ref>. In contrast, the LPA<sub>1</sub> receptor has also been found to induce protective functions in the presence of a particular illness. For example, in patients with heart disease, LPA<sub>1</sub> has been found to communicate with [[PI3K]], [https://en.wikipedia.org/wiki/Protein_kinase_B PKB], and [[ERK]] to create a hypertrophic response in the heart in order to offset reduced heart contractions.<br />
<br />
== Receptor Comparison ==<br />
<br />
=== Sphingosine 1-Phosphate Receptor ===<br />
LPA<sub>1</sub> belongs to the EDG (endothelial differentiation gene) family of [https://en.wikipedia.org/wiki/Lysophospholipid_receptor lysophospholipid receptors]. This family also includes the [https://en.wikipedia.org/wiki/S1PR1 sphingosine 1-phosphate receptor 1] (S1P<sub>1</sub>), which has many structural similarities to LPA<sub>1</sub>. In fact, the transmembrane regions share a sequence identity of 41%. A defining difference between these two receptors is their mode of ligand access to the binding site. Where as the hydrophobic [https://en.wikipedia.org/wiki/Sphingosine-1-phosphate S1P ligand] enters S1P<sub>1</sub> via the membrane, LPA<sub>1</sub> has an extracellular opening that allows LPA access from the extracellular space <ref name="regpeps">PMID: 26091040</ref>. Structural evidence for this altered ligand pathway include global changes in the positioning of the extracellular loops (ECL) and transmembrane helices (TM). Specifically, this includes slight divergence of <scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene>, which is positioned 3 angstroms closer to TMVII compared to S1P<sub>1</sub>, and a repositioning of <scene name='72/721543/Ecl_regions/1'>ECL3</scene>, resulting in a divergence of 8 angstroms from S1P<sub>1</sub> <ref name="regpeps">PMID: 26091040</ref>. This narrowing of the gap between TMI and TMVII blocks membrane ligand access, while the greater distance between ECL3 and the other extracellular loops promotes extracellular access. Additionally, ECL0 is helical in S1P<sub>1</sub>, but lacks secondary structure in LPA<sub>1</sub>. This increased flexibility that results further promotes favorable access from the extracellular space <ref name="regpeps">PMID: 26091040</ref>.<br />
<br />
<br />
<br />
=== Endocannabinoid Receptor 1 ===<br />
LPA<sub>1</sub> also is closely related to the [http://www.nature.com/ijo/journal/v30/n1s/full/0803272a.html cannabinoid receptor]. This close relation gives CB<sub>1</sub> ([[Cannabinoid Receptor 1]]) the ability to bind to analogs of LPA and vice versa, which opens the possibility of metabolic crosstalk between the two signaling systems. This connection is made possible through ligand phosphorylation and dephosphorylation. Specifically, complementary access to the LPA<sub>1</sub> binding pocket can be achieved by phosphorylated CB<sub>1</sub> ligand analogs, while complementary access to the CB<sub>1</sub> binding site requires dephosphorylation of LPA<sub>1</sub> ligand analogs. In both cases, a ligand could serve as a primary [https://en.wikipedia.org/wiki/Selective_receptor_modulator receptor modulator] and a simultaneous [https://en.wikipedia.org/wiki/Prodrug prodrug] for a different receptor.<br />
<br />
<scene name='72/721543/Asp129_and_trp210/2'>Residues Asp129 and Trp210</scene> located within the hydrophobic binding pocket of LPA<sub>1</sub> may share responsibility for the preference for long unsaturated acyl chains. These residues are also interesting in regard to GPCR phylogenic evolution (reference). Trp210 specifically only occurs in this position in 1% of all class A GPCR receptors and is unique to lysophospholipid and cannabinoid receptors. A model for lipid agonist binding generated through molecular modeling was used to dock two of the cannabinoid receptor CB<sub>1</sub>'s most abundant endogenous ligands into the LPA<sub>1</sub> binding pocket. Rotameric shifts of Trp210 and Trp271 leading to expansion of the binding pocket and the exposure of the π clouds of their indole rings provided favorable interactions with the double bonds of the phosphorylated cannabinoid ligands. This favorable binding provides evidence that the hydrophobic binding pockets of LPA<sub>1</sub> and CB<sub>1</sub> are able to favorably bind the same poly-unsaturated acyl chains with metabolically interconvertible head groups.<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Chandler Mitchellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1172&diff=2585017Sandbox Reserved 11722016-03-30T05:11:43Z<p>Chandler Mitchell: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Central_Metabolism}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Lysophosphatidic Acid Receptor 1==<br />
<StructureSection load='4z34' size='340' side='right' caption='Cartoon representation of the LPA1 protein and its antagonist, ON7, colored in white. ([https://en.wikipedia.org/wiki/Protein_Data_Bank PDB] code [http://www.rcsb.org/pdb/explore/explore.do?structureId=4z34 4Z34]) ' scene='72/721543/Overallrainbow/1'><br />
<br />
<br />
== Introduction ==<br />
Lysophosphatidic Acid Receptor 1 (commonly referred to as LPA<sub>1</sub>) is a [[G protein-coupled receptor]] and one of 6 different LPA receptors (LPA<sub>1</sub>-LPA<sub>6</sub>) that bind the phospholipid derivative [https://en.wikipedia.org/wiki/Lysophosphatidic_acid lysophosphatidic acid (LPA)], a signaling molecule that acts as a potent [https://en.wikipedia.org/wiki/Mitogen mitogen] upon binding to one of its six receptors.<ref name="regpeps">PMID: 26091040</ref>, ----------- LPA<sub>1</sub> is part of the larger EDG receptor family(link) which includes the more widely known sphingosine 1-phopshate receptors.<br />
== Structure ==<br />
[[Image:ABP.png|250 px|left|thumb|Electrostatic illustration of the amphipathic binding pocket of the LPA<sub>1</sub> receptor.]]<br />
The LPA<sub>1</sub> receptor protein is composed of 364 amino acids with a mass of approximately 41 kDa. Just as other G-protein coupled receptors, LPA<sub>1</sub> contains seven [http://kinemage.biochem.duke.edu/teaching/anatax/html/anatax.2a.html alpha helices] which make up the seven transmembrane spanning domains with three intracellular loops and three extracellular loops. The amino terminus of this protein is located on the extracellular side of the membrane, while the carboxyl terminus is located on the intracellular side of the membrane.<ref name = 'Hernández-Méndez'>Hernández-Méndez, Aurelio, Rocío Alcántara-Hernández, and J. Adolfo García-Sáinz. "Lysophosphatidic Acid LPA1-3 Receptors: Signaling, Regulation and in Silico Analysis of Their Putative Phosphorylation Sites." Receptors & Clinical Investigation Receptor Clin Invest 1.3 (2014). Web. 15 Feb. 2016.' </ref>. Within these helices is an amphipathic binding pocket which stabilizes the binding of its ligand, LPA.<br />
=== Key Ligand Interactions ===<br />
[[Image:ON7.png|250 px|right|thumb|Overall structure of the LPA<sub>1</sub> receptor in tan interacting with its antagonist, ON7, shown in green and red sticks.]]<br />
Three separate interactions with an antagonist of LPA<sub>1</sub>, ON7, help demonstrate the key interactions that stabilize the binding of the LPA phospholipid to this receptor. At the polar region of the binding pocket, the majority of this region is stabilized by <scene name='72/721543/Arg124gln125/1'>Arg124 and Gln125</scene> forming ionic and polar interactions with the carboxylic acid and the hydroxyl group of ON7.<ref name="regpeps">PMID: 26091040</ref> In addition, interplay between <scene name='72/721543/Lys39_and_glu293/4'>Glu293 and Lys39</scene> causes another stabilizing component of the ON7 antagonist. Glu293 forms polar interactions with Lys39, positioning it in close proximity to to the carboxylic acid of ON7, which then interactions with Lys39 via ionic bonding.<ref name="regpeps">PMID: 26091040</ref> While Lys39 is highly conserved among all six LPA receptors, a His40 residue is present that is specific to the LPA<sub>1</sub> receptor. <scene name='72/721543/His40/1'>His40</scene> forms both ionic and polar interactions with the carboxylic acid of ON7. The protonation of this residue has been found to greatly affect the binding affinity of LPA, and is an important link to tumor growth and survival in acidic environments.<ref name="regpeps">PMID: 26091040</ref><br />
<br />
<br />
== Function ==<br />
The LPA<sub>1</sub> receptor is present in nearly all cells and tissues throughout the body, and deletion of the LPA<sub>1</sub> receptor has been found to have physiological effects on every organ system, indicating its wide range of functions. Specifically, this receptor has been found to initiate downstream signaling cascades with three G<sub>α</sub> proteins: G<sub>i/o</sub>, G<sub>q/11</sub>, and G<sub>12/13</sub>. These G<sub>α</sub> proteins begin signaling cascades with molecules such as [https://en.wikipedia.org/wiki/Phospholipase_C phospholipase C] and [[MAPK]] that signal for cell proliferation, survival, and migration. <ref name = 'Yung'>Yung, Y. C., N. C. Stoddard, and J. Chun. "LPA Receptor Signaling: Pharmacology, Physiology, and Pathophysiology." The Journal of Lipid Research 55.7 (2014): 1192-214. Web. 17 Feb. 2016.' </ref>.Despite this receptor being expressed throughout the body, LPA<sub>1</sub> has been found to be expressed highly in neural tissue, aiding in several different neurodevelopmental processes including growth and folding of the [https://www.dartmouth.edu/~rswenson/NeuroSci/chapter_11.html cerebral cortex] and the growth, survival, and migration of neural [https://en.wikipedia.org/wiki/Progenitor_cell progenitor cells] through its different [https://en.wikipedia.org/wiki/G_protein link G-protein] regulated pathways.<ref name = 'Chun'>Chun, J., Hla, T., Spiegel, S., and Moolenaar, W.H. “Lysophospholipid Receptors: Signaling and Biochemistry.” John Wiley & Sons, Inc. (2013) pp.i-xviii. 5 Feb. 2016.' </ref>. Finally, LPA1 receptors expressed in neural tissue aid in Schwann cell migration and myelination through a signaling pathway with the [https://en.wikipedia.org/wiki/RAC1 Rac1] G-protein.<ref name="number5">PMID: 24115248</ref>.<br />
<br />
<br />
== Disease Relevance ==<br />
Because LPA<sub>1</sub> is expressed in so many tissues throughout the body, it has been linked to the symptoms and progression of several different diseases and disorders. For example, due to LPA<sub>1</sub>'s role in pain signaling, overexpression of this protein can cause both [https://en.wikipedia.org/wiki/Allodynia allodynia] or [https://en.wikipedia.org/wiki/Hyperalgesia hyperalgesia], common symptoms of multiple sclerosis or strokes. In addition, since LPA<sub>1</sub> helps in the myelination of Schwann cells, mutation of the receptor can also lead to a decrease in [https://en.wikipedia.org/wiki/Prepulse_inhibition prepulse inhibition], a general sign of schizophrenia.<ref name="number6">PMID: 20331961</ref>.Lastly, because of the mitogen signaling activity of LPA<sub>1</sub>, abnormal expression or mutation of this receptor has been linked to tumor growth, survival, and migration in both liver and lung tumors. As recently discussed, the His40 on LPA<sub>1</sub>, when protonated, increased LPA binding affinity is increase by up to 1kcal/mol. Because of this, in an acidic environment that is typically produced by [https://en.wikipedia.org/wiki/Tumor_hypoxia hypoxic tumors] creating lactic acid, LPA<sub>1</sub> activity is increased, allowing these tumors to continue to proliferate, migrate, and survive.<ref name="number7">PMID: 24367336</ref>. In contrast, the LPA<sub>1</sub> receptor has also been found to induce protective functions in the presence of a particular illness. For example, in patients with heart disease, LPA<sub>1</sub> has been found to communicate with [[PI3K]], [https://en.wikipedia.org/wiki/Protein_kinase_B PKB], and [[ERK]] to create a hypertrophic response in the heart in order to offset reduced heart contractions.<br />
<br />
== Receptor Comparison ==<br />
<br />
=== Sphingosine 1-Phosphate Receptor ===<br />
LPA<sub>1</sub> belongs to the EDG (endothelial differentiation gene) family of [https://en.wikipedia.org/wiki/Lysophospholipid_receptor lysophospholipid receptors]. This family also includes the [https://en.wikipedia.org/wiki/S1PR1 sphingosine 1-phosphate receptor 1] (S1P<sub>1</sub>), which has many structural similarities to LPA<sub>1</sub>. In fact, the transmembrane regions share a sequence identity of 41%. A defining difference between these two receptors is their mode of ligand access to the binding site. Where as the hydrophobic [https://en.wikipedia.org/wiki/Sphingosine-1-phosphate S1P ligand] enters S1P<sub>1</sub> via the membrane, LPA<sub>1</sub> has an extracellular opening that allows LPA access from the extracellular space. Structural evidence for this altered ligand pathway include global changes in the positioning of the extracellular loops (ECL) and transmembrane helices (TM). Specifically, this includes slight divergence of <scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene>, which is positioned 3 angstroms closer to TMVII compared to S1P<sub>1</sub>, and a repositioning of <scene name='72/721543/Ecl_regions/1'>ECL3</scene>, resulting in a divergence of 8 angstroms from S1P<sub>1</sub>. This narrowing of the gap between TMI and TMVII blocks membrane ligand access, while the greater distance between ECL3 and the other extracellular loops promotes extracellular access. Additionally, ECL0 is helical in S1P<sub>1</sub>, but lacks secondary structure in LPA<sub>1</sub>. This increased flexibility that results further promotes favorable access from the extracellular space.<br />
<br />
<br />
<br />
=== Endocannabinoid Receptor 1 ===<br />
LPA<sub>1</sub> also is closely related to the [http://www.nature.com/ijo/journal/v30/n1s/full/0803272a.html cannabinoid receptor]. This close relation gives CB<sub>1</sub> ([[Cannabinoid Receptor 1]]) the ability to bind to analogs of LPA and vice versa, which opens the possibility of metabolic crosstalk between the two signaling systems. This connection is made possible through ligand phosphorylation and dephosphorylation. Specifically, complementary access to the LPA<sub>1</sub> binding pocket can be achieved by phosphorylated CB<sub>1</sub> ligand analogs, while complementary access to the CB<sub>1</sub> binding site requires dephosphorylation of LPA<sub>1</sub> ligand analogs. In both cases, a ligand could serve as a primary [https://en.wikipedia.org/wiki/Selective_receptor_modulator receptor modulator] and a simultaneous [https://en.wikipedia.org/wiki/Prodrug prodrug] for a different receptor.<br />
<br />
<scene name='72/721543/Asp129_and_trp210/2'>Residues Asp129 and Trp210</scene> located within the hydrophobic binding pocket of LPA<sub>1</sub> may share responsibility for the preference for long unsaturated acyl chains. These residues are also interesting in regard to GPCR phylogenic evolution (reference). Trp210 specifically only occurs in this position in 1% of all class A GPCR receptors and is unique to lysophospholipid and cannabinoid receptors. A model for lipid agonist binding generated through molecular modeling was used to dock two of the cannabinoid receptor CB<sub>1</sub>'s most abundant endogenous ligands into the LPA<sub>1</sub> binding pocket. Rotameric shifts of Trp210 and Trp271 leading to expansion of the binding pocket and the exposure of the π clouds of their indole rings provided favorable interactions with the double bonds of the phosphorylated cannabinoid ligands. This favorable binding provides evidence that the hydrophobic binding pockets of LPA<sub>1</sub> and CB<sub>1</sub> are able to favorably bind the same poly-unsaturated acyl chains with metabolically interconvertible head groups.<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Chandler Mitchellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1172&diff=2585014Sandbox Reserved 11722016-03-30T05:07:30Z<p>Chandler Mitchell: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Central_Metabolism}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Lysophosphatidic Acid Receptor 1==<br />
<StructureSection load='4z34' size='340' side='right' caption='Cartoon representation of the LPA1 protein and its antagonist, ON7, colored in white. ([https://en.wikipedia.org/wiki/Protein_Data_Bank PDB] code [http://www.rcsb.org/pdb/explore/explore.do?structureId=4z34 4Z34]) ' scene='72/721543/Overallrainbow/1'><br />
<br />
<br />
== Introduction ==<br />
Lysophosphatidic Acid Receptor 1 (commonly referred to as LPA<sub>1</sub>) is a [[G protein-coupled receptor]] and one of 6 different LPA receptors (LPA<sub>1</sub>-LPA<sub>6</sub>) that bind the phospholipid derivative [https://en.wikipedia.org/wiki/Lysophosphatidic_acid lysophosphatidic acid (LPA)], a signaling molecule that acts as a potent [https://en.wikipedia.org/wiki/Mitogen mitogen] upon binding to one of its six receptors.<ref name="regpeps">PMID: 26091040</ref>, ----------- LPA<sub>1</sub> is part of the larger EDG receptor family(link) which includes the more widely known sphingosine 1-phopshate receptors.<br />
== Structure ==<br />
[[Image:ABP.png|250 px|left|thumb|Electrostatic illustration of the amphipathic binding pocket of the LPA<sub>1</sub> receptor.]]<br />
The LPA<sub>1</sub> receptor protein is composed of 364 amino acids with a mass of approximately 41 kDa. Just as other G-protein coupled receptors, LPA<sub>1</sub> contains seven [http://kinemage.biochem.duke.edu/teaching/anatax/html/anatax.2a.html alpha helices] which make up the seven transmembrane spanning domains with three intracellular loops and three extracellular loops. The amino terminus of this protein is located on the extracellular side of the membrane, while the carboxyl terminus is located on the intracellular side of the membrane.<ref name = 'Hernández-Méndez'>Hernández-Méndez, Aurelio, Rocío Alcántara-Hernández, and J. Adolfo García-Sáinz. "Lysophosphatidic Acid LPA1-3 Receptors: Signaling, Regulation and in Silico Analysis of Their Putative Phosphorylation Sites." Receptors & Clinical Investigation Receptor Clin Invest 1.3 (2014). Web. 15 Feb. 2016.' </ref>. Within these helices is an amphipathic binding pocket which stabilizes the binding of its ligand, LPA.<br />
=== Key Ligand Interactions ===<br />
[[Image:ON7.png|250 px|right|thumb|Overall structure of the LPA<sub>1</sub> receptor in tan interacting with its antagonist, ON7, shown in green and red sticks.]]<br />
Three separate interactions with an antagonist of LPA<sub>1</sub>, ON7, help demonstrate the key interactions that stabilize the binding of the LPA phospholipid to this receptor. At the polar region of the binding pocket, the majority of this region is stabilized by <scene name='72/721543/Arg124gln125/1'>Arg124 and Gln125</scene> forming ionic and polar interactions with the carboxylic acid and the hydroxyl group of ON7.<ref name="regpeps">PMID: 26091040</ref> In addition, interplay between <scene name='72/721543/Lys39_and_glu293/4'>Glu293 and Lys39</scene> causes another stabilizing component of the ON7 antagonist. Glu293 forms polar interactions with Lys39, positioning it in close proximity to to the carboxylic acid of ON7, which then interactions with Lys39 via ionic bonding.<ref name="regpeps">PMID: 26091040</ref> While Lys39 is highly conserved among all six LPA receptors, a His40 residue is present that is specific to the LPA<sub>1</sub> receptor. <scene name='72/721543/His40/1'>His40</scene> forms both ionic and polar interactions with the carboxylic acid of ON7. The protonation of this residue has been found to greatly affect the binding affinity of LPA, and is an important link to tumor growth and survival in acidic environments.<ref name="regpeps">PMID: 26091040</ref><br />
<br />
<br />
== Function ==<br />
The LPA<sub>1</sub> receptor is present in nearly all cells and tissues throughout the body, and deletion of the LPA<sub>1</sub> receptor has been found to have physiological effects on every organ system, indicating its wide range of functions. Specifically, this receptor has been found to initiate downstream signaling cascades with three G<sub>α</sub> proteins: G<sub>i/o</sub>, G<sub>q/11</sub>, and G<sub>12/13</sub>. These G<sub>α</sub> proteins begin signaling cascades with molecules such as [https://en.wikipedia.org/wiki/Phospholipase_C phospholipase C] and [[MAPK]] that signal for cell proliferation, survival, and migration. <ref name = 'Yung'>Yung, Y. C., N. C. Stoddard, and J. Chun. "LPA Receptor Signaling: Pharmacology, Physiology, and Pathophysiology." The Journal of Lipid Research 55.7 (2014): 1192-214. Web. 17 Feb. 2016.' </ref>.Despite this receptor being expressed throughout the body, LPA<sub>1</sub> has been found to be expressed highly in neural tissue, aiding in several different neurodevelopmental processes including growth and folding of the [https://www.dartmouth.edu/~rswenson/NeuroSci/chapter_11.html cerebral cortex] and the growth, survival, and migration of neural [https://en.wikipedia.org/wiki/Progenitor_cell progenitor cells] through its different [https://en.wikipedia.org/wiki/G_protein link G-protein] regulated pathways.<ref name = 'Chun'>Chun, J., Hla, T., Spiegel, S., and Moolenaar, W.H. “Lysophospholipid Receptors: Signaling and Biochemistry.” John Wiley & Sons, Inc. (2013) pp.i-xviii. 5 Feb. 2016.' </ref>. Finally, LPA1 receptors expressed in neural tissue aid in Schwann cell migration and myelination through a signaling pathway with the [https://en.wikipedia.org/wiki/RAC1 Rac1] G-protein.<ref name="number5">PMID: 24115248</ref>.<br />
<br />
<br />
== Disease Relevance ==<br />
Because LPA<sub>1</sub> is expressed in so many tissues throughout the body, it has been linked to the symptoms and progression of several different diseases and disorders. For example, due to LPA<sub>1</sub>'s role in pain signaling, overexpression of this protein can cause both [https://en.wikipedia.org/wiki/Allodynia allodynia] or [https://en.wikipedia.org/wiki/Hyperalgesia hyperalgesia], common symptoms of multiple sclerosis or strokes. In addition, since LPA<sub>1</sub> helps in the myelination of Schwann cells, mutation of the receptor can also lead to a decrease in [https://en.wikipedia.org/wiki/Prepulse_inhibition prepulse inhibition], a general sign of schizophrenia.<ref name="number6">PMID: 20331961</ref>.Lastly, because of the mitogen signaling activity of LPA<sub>1</sub>, abnormal expression or mutation of this receptor has been linked to tumor growth, survival, and migration in both liver and lung tumors. As recently discussed, the His40 on LPA<sub>1</sub>, when protonated, increased LPA binding affinity is increase by up to 1kcal/mol. Because of this, in an acidic environment that is typically produced by [https://en.wikipedia.org/wiki/Tumor_hypoxia hypoxic tumors] creating lactic acid, LPA<sub>1</sub> activity is increased, allowing these tumors to continue to proliferate, migrate, and survive.<ref name="number7">PMID: 24367336</ref>. In contrast, the LPA<sub>1</sub> receptor has also been found to induce protective functions in the presence of a particular illness. For example, in patients with heart disease, LPA<sub>1</sub> has been found to communicate with [[PI3K]], [https://en.wikipedia.org/wiki/Protein_kinase_B PKB], and [[ERK]] to create a hypertrophic response in the heart in order to offset reduced heart contractions.<br />
<br />
== Receptor Comparison ==<br />
<br />
=== Sphingosine 1-Phosphate Receptor ===<br />
LPA<sub>1</sub> belongs to the EDG (endothelial differentiation gene) family of [https://en.wikipedia.org/wiki/Lysophospholipid_receptor lysophospholipid receptors]. This family also includes the [https://en.wikipedia.org/wiki/S1PR1 sphingosine 1-phosphate receptor 1] (S1P<sub>1</sub>), which has many structural similarities to LPA<sub>1</sub>. In fact, the transmembrane regions share a sequence identity of 41%. A defining difference between these two receptors is their mode of ligand access to the binding site. Where as the hydrophobic [https://en.wikipedia.org/wiki/Sphingosine-1-phosphate S1P ligand] enters S1P<sub>1</sub> via the membrane, LPA<sub>1</sub> has an extracellular opening that allows LPA access from the extracellular space. Structural evidence for this altered ligand pathway include global changes in the positioning of the extracellular loops (ECL) and transmembrane helices (TM). Specifically, this includes slight divergence of <scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene>, which is positioned 3 angstroms closer to TMVII compared to S1P<sub>1</sub>, and a repositioning of <scene name='72/721543/Ecl_regions/1'>ECL3</scene>, resulting in a divergence of 8 angstroms from S1P<sub>1</sub>. This narrowing of the gap between TMI and TMVII blocks membrane ligand access, while the greater distance between ECL3 and the other extracellular loops promotes extracellular access. Additionally, ECL0 is helical in S1P<sub>1</sub>, but lacks secondary structure in LPA<sub>1</sub>. This increased flexibility that results further promotes favorable access from the extracellular space.<br />
<br />
<scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene><br />
<br />
<scene name='72/721543/Ecl_regions/1'>ECL3</scene><br />
<br />
=== Endocannabinoid Receptor 1 ===<br />
LPA<sub>1</sub> also is closely related to the [http://www.nature.com/ijo/journal/v30/n1s/full/0803272a.html cannabinoid receptor]. This close relation gives CB<sub>1</sub> ([[Cannabinoid Receptor 1]]) the ability to bind to analogs of LPA and vice versa, which opens the possibility of metabolic crosstalk between the two signaling systems. This connection is made possible through ligand phosphorylation and dephosphorylation. Specifically, complementary access to the LPA<sub>1</sub> binding pocket can be achieved by phosphorylated CB<sub>1</sub> ligand analogs, while complementary access to the CB<sub>1</sub> binding site requires dephosphorylation of LPA<sub>1</sub> ligand analogs. In both cases, a ligand could serve as a primary [https://en.wikipedia.org/wiki/Selective_receptor_modulator receptor modulator] and a simultaneous [https://en.wikipedia.org/wiki/Prodrug prodrug] for a different receptor.<br />
<br />
<scene name='72/721543/Asp129_and_trp210/2'>Residues Asp129 and Trp210</scene> located within the hydrophobic binding pocket of LPA<sub>1</sub> may share responsibility for the preference for long unsaturated acyl chains. These residues are also interesting in regard to GPCR phylogenic evolution (reference). Trp210 specifically only occurs in this position in 1% of all class A receptors and is unique to lysophospholipid and cannabinoid receptors. A model for lipid agonist binding generated through molecular modeling was used to dock two of the cannabinoid receptor CB<sub>1</sub>'s most abundant endogenous ligands into the LPA<sub>1</sub> binding pocket. Rotameric shifts of Trp210 and Trp271 leading to expansion of the binding pocket and the exposure of the π clouds of their indole rings provided favorable interactions with the double bonds of the phosphorylated cannabinoid ligands. This favorable binding provides evidence that the hydrophobic binding pockets of LPA<sub>1</sub> and CB<sub>1</sub> are able to favorably bind the same poly-unsaturated acyl chains with metabolically interconvertible head groups.<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Chandler Mitchellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1172&diff=2585011Sandbox Reserved 11722016-03-30T04:43:17Z<p>Chandler Mitchell: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Central_Metabolism}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Lysophosphatidic Acid Receptor 1==<br />
<StructureSection load='4z34' size='340' side='right' caption='Cartoon representation of the LPA1 protein and its antagonist, ON7, colored in white. ([https://en.wikipedia.org/wiki/Protein_Data_Bank PDB] code [http://www.rcsb.org/pdb/explore/explore.do?structureId=4z34 4Z34]) ' scene='72/721543/Overallrainbow/1'><br />
<br />
<br />
== Introduction ==<br />
Lysophosphatidic Acid Receptor 1 (commonly referred to as LPA<sub>1</sub>) is a [[G protein-coupled receptor]] and one of 6 different LPA receptors (LPA<sub>1</sub>-LPA<sub>6</sub>) that bind the phospholipid derivative [https://en.wikipedia.org/wiki/Lysophosphatidic_acid lysophosphatidic acid (LPA)], a signaling molecule that acts as a potent [https://en.wikipedia.org/wiki/Mitogen mitogen] upon binding to one of its six receptors.<ref name="regpeps">PMID: 26091040</ref>, ----------- LPA<sub>1</sub> is part of the larger EDG receptor family(link) which includes the more widely known sphingosine 1-phopshate receptors.<br />
== Structure ==<br />
[[Image:ABP.png|250 px|left|thumb|Electrostatic illustration of the amphipathic binding pocket of the LPA<sub>1</sub> receptor.]]<br />
The LPA<sub>1</sub> receptor protein is composed of 364 amino acids with a mass of approximately 41 kDa. Just as other G-protein coupled receptors, LPA<sub>1</sub> contains seven [http://kinemage.biochem.duke.edu/teaching/anatax/html/anatax.2a.html alpha helices] which make up the seven transmembrane spanning domains with three intracellular loops and three extracellular loops. The amino terminus of this protein is located on the extracellular side of the membrane, while the carboxyl terminus is located on the intracellular side of the membrane.<ref name = 'Hernández-Méndez'>Hernández-Méndez, Aurelio, Rocío Alcántara-Hernández, and J. Adolfo García-Sáinz. "Lysophosphatidic Acid LPA1-3 Receptors: Signaling, Regulation and in Silico Analysis of Their Putative Phosphorylation Sites." Receptors & Clinical Investigation Receptor Clin Invest 1.3 (2014). Web. 15 Feb. 2016.' </ref>. Within these helices is an amphipathic binding pocket which stabilizes the binding of its ligand, LPA.<br />
=== Key Ligand Interactions ===<br />
[[Image:ON7.png|250 px|right|thumb|Overall structure of the LPA<sub>1</sub> receptor in tan interacting with its antagonist, ON7, shown in green and red sticks.]]<br />
Three separate interactions with an antagonist of LPA<sub>1</sub>, ON7, help demonstrate the key interactions that stabilize the binding of the LPA phospholipid to this receptor. At the polar region of the binding pocket, the majority of this region is stabilized by <scene name='72/721543/Arg124gln125/1'>Arg124 and Gln125</scene> forming ionic and polar interactions with the carboxylic acid and the hydroxyl group of ON7.<ref name="regpeps">PMID: 26091040</ref> In addition, interplay between <scene name='72/721543/Lys39_and_glu293/4'>Glu293 and Lys39</scene> causes another stabilizing component of the ON7 antagonist. Glu293 forms polar interactions with Lys39, positioning it in close proximity to to the carboxylic acid of ON7, which then interactions with Lys39 via ionic bonding.<ref name="regpeps">PMID: 26091040</ref> While Lys39 is highly conserved among all six LPA receptors, a His40 residue is present that is specific to the LPA<sub>1</sub> receptor. <scene name='72/721543/His40/1'>His40</scene> forms both ionic and polar interactions with the carboxylic acid of ON7. The protonation of this residue has been found to greatly affect the binding affinity of LPA, and is an important link to tumor growth and survival in acidic environments.<ref name="regpeps">PMID: 26091040</ref><br />
<br />
<br />
== Function ==<br />
The LPA<sub>1</sub> receptor is present in nearly all cells and tissues throughout the body, and deletion of the LPA<sub>1</sub> receptor has been found to have physiological effects on every organ system, indicating its wide range of functions. Specifically, this receptor has been found to initiate downstream signaling cascades with three G<sub>α</sub> proteins: G<sub>i/o</sub>, G<sub>q/11</sub>, and G<sub>12/13</sub>. These G<sub>α</sub> proteins begin signaling cascades with molecules such as [https://en.wikipedia.org/wiki/Phospholipase_C phospholipase C] and [[MAPK]] that signal for cell proliferation, survival, and migration. <ref name = 'Yung'>Yung, Y. C., N. C. Stoddard, and J. Chun. "LPA Receptor Signaling: Pharmacology, Physiology, and Pathophysiology." The Journal of Lipid Research 55.7 (2014): 1192-214. Web. 17 Feb. 2016.' </ref>.Despite this receptor being expressed throughout the body, LPA<sub>1</sub> has been found to be expressed highly in neural tissue, aiding in several different neurodevelopmental processes including growth and folding of the [https://www.dartmouth.edu/~rswenson/NeuroSci/chapter_11.html cerebral cortex] and the growth, survival, and migration of neural [https://en.wikipedia.org/wiki/Progenitor_cell progenitor cells] through its different [https://en.wikipedia.org/wiki/G_protein link G-protein] regulated pathways.<ref name = 'Chun'>Chun, J., Hla, T., Spiegel, S., and Moolenaar, W.H. “Lysophospholipid Receptors: Signaling and Biochemistry.” John Wiley & Sons, Inc. (2013) pp.i-xviii. 5 Feb. 2016.' </ref>. Finally, LPA1 receptors expressed in neural tissue aid in Schwann cell migration and myelination through a signaling pathway with the [https://en.wikipedia.org/wiki/RAC1 Rac1] G-protein.<ref name="number5">PMID: 24115248</ref>.<br />
<br />
<br />
== Disease Relevance ==<br />
Because LPA<sub>1</sub> is expressed in so many tissues throughout the body, it has been linked to the symptoms and progression of several different diseases and disorders. For example, due to LPA<sub>1</sub>'s role in pain signaling, overexpression of this protein can cause both [https://en.wikipedia.org/wiki/Allodynia allodynia] or [https://en.wikipedia.org/wiki/Hyperalgesia hyperalgesia], common symptoms of multiple sclerosis or strokes. In addition, since LPA<sub>1</sub> helps in the myelination of Schwann cells, mutation of the receptor can also lead to a decrease in [https://en.wikipedia.org/wiki/Prepulse_inhibition prepulse inhibition], a general sign of schizophrenia.<ref name="number6">PMID: 20331961</ref>.Lastly, because of the mitogen signaling activity of LPA<sub>1</sub>, abnormal expression or mutation of this receptor has been linked to tumor growth, survival, and migration in both liver and lung tumors. As recently discussed, the His40 on LPA<sub>1</sub>, when protonated, increased LPA binding affinity is increase by up to 1kcal/mol. Because of this, in an acidic environment that is typically produced by [https://en.wikipedia.org/wiki/Tumor_hypoxia hypoxic tumors] creating lactic acid, LPA<sub>1</sub> activity is increased, allowing these tumors to continue to proliferate, migrate, and survive.<ref name="number7">PMID: 24367336</ref>. In contrast, the LPA<sub>1</sub> receptor has also been found to induce protective functions in the presence of a particular illness. For example, in patients with heart disease, LPA<sub>1</sub> has been found to communicate with [[PI3K]], [https://en.wikipedia.org/wiki/Protein_kinase_B PKB], and [[ERK]] to create a hypertrophic response in the heart in order to offset reduced heart contractions.<br />
<br />
== Receptor Comparison ==<br />
<br />
=== Sphingosine 1-Phosphate Receptor ===<br />
LPA<sub>1</sub> belongs to the EDG (endothelial differentiation gene) family of [https://en.wikipedia.org/wiki/Lysophospholipid_receptor lysophospholipid receptors]. This family also includes the [https://en.wikipedia.org/wiki/S1PR1 sphingosine 1-phosphate receptor 1] (S1P<sub>1</sub>), which has many structural similarities to LPA<sub>1</sub>. In fact, the transmembrane regions share a sequence identity of 41%. A defining difference between these two receptors is their mode of ligand access to the binding site. Where as the hydrophobic [https://en.wikipedia.org/wiki/Sphingosine-1-phosphate S1P ligand] enters S1P<sub>1</sub> via the membrane, LPA<sub>1</sub> has an extracellular opening that allows LPA access from the extracellular space. Structural evidence for this altered ligand pathway include global changes in the positioning of the extracellular loops (ECL) and transmembrane helices (TM). Specifically, this includes slight divergence of <scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene>, which is positioned 3 angstroms closer to TMVII compared to S1P<sub>1</sub>, and a repositioning of <scene name='72/721543/Ecl_regions/1'>ECL3</scene>, resulting in a divergence of 8 angstroms from S1P<sub>1</sub>. This narrowing of the gap between TMI and TMVII blocks membrane ligand access, while the greater distance between ECL3 and the other extracellular loops promotes extracellular access. Additionally, ECL0 is helical in S1P<sub>1</sub>, but lacks secondary structure in LPA<sub>1</sub>. This increased flexibility that results further promotes favorable access from the extracellular space.<br />
<br />
<scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene><br />
<br />
<scene name='72/721543/Ecl_regions/1'>ECL3</scene><br />
<br />
=== Endocannabinoid Receptor 1 ===<br />
LPA<sub>1</sub> also is closely related to the [http://www.nature.com/ijo/journal/v30/n1s/full/0803272a.html cannabinoid receptor] [https://en.wikipedia.org/wiki/Cannabinoid_receptor_type_1 CB<sub>1</sub>]. This close relation gives CB<sub>1</sub> the ability to bind to analogs of LPA and vice versa, which opens the possibility of metabolic crosstalk between the two signaling systems. This connection is made possible through ligand phosphorylation and dephosphorylation. Specifically, complementary access to the LPA<sub>1</sub> binding pocket can be achieved by phosphorylated CB<sub>1</sub> ligand analogs, while complementary access to the CB<sub>1</sub> binding site required dephosphorylation of LPA<sub>1</sub> ligand analogs. In both cases, a ligand could serve as a primary receptor modulator and a simultaneous prodrug for a different receptor.<br />
<br />
<scene name='72/721543/Asp129_and_trp210/2'>Residues Asp129 and Trp210</scene> located within the hydrophobic binding pocket of LPA<sub>1</sub> may share responsibility for the preference for long unsaturated acyl chains. These residues are also interesting in regard to GPCR phylogenic evolution (reference). Trp210 specifically only occurs in this position in 1% of all class A receptors and is unique to lysophospholipid and cannabinoid receptors. A model for lipid agonist binding generated through molecular modeling was used to dock two of the cannabinoid receptor CB<sub>1</sub>'s most abundant endogenous ligands into the LPA<sub>1</sub> binding pocket. Rotameric shifts of Trp210 and Trp271 leading to expansion of the binding pocket and the exposure of the π clouds of their indole rings provided favorable interactions with the double bonds of the phosphorylated cannabinoid ligands. This favorable binding provides evidence that the hydrophobic binding pockets of LPA<sub>1</sub> and CB<sub>1</sub> are able to favorably bind the same poly-unsaturated acyl chains with metabolically interconvertible head groups.<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Chandler Mitchellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1172&diff=2584755Sandbox Reserved 11722016-03-29T13:43:06Z<p>Chandler Mitchell: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Central_Metabolism}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Lysophosphatidic Acid Receptor 1==<br />
<StructureSection load='4z34' size='340' side='right' caption='Cartoon representation of the LPA1 protein and its antagonist, ON7. ([https://en.wikipedia.org/wiki/Protein_Data_Bank PDB] code [http://www.rcsb.org/pdb/explore/explore.do?structureId=4z34 4Z34]) ' scene='72/721543/Overall/1'><br />
<br />
<br />
== Introduction ==<br />
[[Image:General_Picture.png |200 px|left|thumb| General image of the LPA<sub>1</sub> receptor's seven alpha helices]]<br />
Lysophosphatidic Acid Receptor 1 (commonly referred to as LPA<sub>1</sub>) is a [[G protein-coupled receptor]] and one of 6 different LPA receptors (LPA<sub>1</sub>-LPA<sub>6</sub>) that bind the phospholipid derivative [https://en.wikipedia.org/wiki/Lysophosphatidic_acid lysophosphatidic acid (LPA)], a signaling molecule that acts as a potent mitogen upon binding to one of its six receptors.<ref name="regpeps">PMID: 26091040</ref>, ----------- LPA<sub>1</sub> is part of the larger EDG receptor family(link) which includes the more widely known sphingosine 1-phopshate receptors.<br />
== Structure ==<br />
[[Image:ON7.png|200 px|left|thumb|LPA<sub>1</sub> receptor in tan, antagonist ON7 in green and red]]<br />
The LPA<sub>1</sub> receptor protein is composed of 364 amino acids with a mass of approximately 41 kDa. Just as other G-protein coupled receptors, LPA<sub>1</sub> contains seven alpha helices which make up the seven transmembrane spanning domains with three intracellular loops and three extracellular loops. Within these helices is an amphiphilic binding pocket enabling the LPA molecule to bind.<br />
=== Key Ligand Interactions ===<br />
Three separate interactions with an antagonist of LPA<sub>1</sub>, ON7, help demonstrate the key interactions that stabilize the binding of the LPA phospholipid to this receptor. At the polar region of the binding pocket, the majority of this region is stabilized by <scene name='72/721543/Arg124gln125/1'>Arg124 and Gln125</scene> forming ionic and polar interactions with the carboxylic acid and the hydroxyl group of ON7. In addition, interplay between <scene name='72/721543/Lys39_and_glu293/4'>Glu293 and Lys39</scene> causes another stabilizing component of the ON7 antagonist. Glu293 forms polar interactions with Lys39, positioning it in close proximity to to the carboxylic acid of ON7, which then interactions with Lys39 via ionic bonding. While Lys39 is highly conserved among all six LPA receptors, a His40 residue is present that is specific to the LPA<sub>1</sub> receptor. <scene name='72/721543/His40/1'>His40</scene> forms both ionic and polar interactions with the carboxylic acid of ON7. The protonation of this residue has been found to greatly affect the binding affinity of LPA, and is an important link to tumor growth and survival in acidic environments.<br />
<br />
<br />
== Function ==<br />
The LPA<sub>1</sub> receptor has been found to initiate downstream signaling cascades with three [https://en.wikipedia.org/wiki/G_protein G proteins] that signal for cell proliferation, survival, and migration. The LPA<sub>1</sub> receptor is present in nearly all cells and tissues throughout the body, and deletion of the LPA<sub>1</sub> receptor has been found to have physiological effects on every organ system. Despite this receptor being expressed throughout the body, LPA<sub>1</sub> has been found to be expressed highly in neural tissue, aiding in Schwann cell migration and myelination, formation of synapses, and glial cell growth. Recent studies have also found that the LPA<sub>1</sub> receptor is important in pain signal initiation via a [https://en.wikipedia.org/wiki/Rho-associated_protein_kinase ROCK] pathway.<br />
<br />
== Disease Relevance ==<br />
The LPA<sub>1</sub> receptor, depending on its level of expression, has been linked to both protective functions in the presence of a disease as well as causing a particular illness. For example, in patients with heart diseases, LPA<sub>1</sub> has been found to communicate with [[PI3K]], [https://en.wikipedia.org/wiki/Protein_kinase_B PKB], and [[ERK]] to induce a hypertrophic response in the heart in order to offset reduced heart contractions. In addition, due to LPA<sub>1</sub>'s function of pain signaling, overexertion of this protein can cause both [https://en.wikipedia.org/wiki/Allodynia allodynia] or [https://en.wikipedia.org/wiki/Hyperalgesia hyperalgesia], common symptoms of multiple sclerosis or a stroke.<br />
Because of the mitogen signaling activity of LPA<sub>1</sub>, abnormal expression or mutation of this receptor has been linked to tumor growth, survival, and migration in both liver and lung tumors. As recently discussed, the His40 on LPA<sub>1</sub>, when protonated, increased LPA binding affinity is increase by up to 1kcal/mol. Because of this, in an acidic environment that is typically produced by [https://en.wikipedia.org/wiki/Tumor_hypoxia hypoxic tumors] creating lactic acid, LPA<sub>1</sub> activity is increased, allowing these tumors to continue to proliferate, migrate, and survive. Lastly, due to the function of LPA<sub>1</sub> in myelinating Schwann cells, mutation of the receptor can also lead to a decrease in [https://en.wikipedia.org/wiki/Prepulse_inhibition prepulse inhibition], a general sign of schizophrenia.<br />
<br />
== Receptor Comparison ==<br />
<br />
=== Sphingosine 1-Phosphate Receptor ===<br />
LPA<sub>1</sub> belongs to the EDG (endothelial differentiation gene) family of [https://en.wikipedia.org/wiki/Lysophospholipid_receptor lysophospholipid receptors]. This family also includes the [https://en.wikipedia.org/wiki/S1PR1 sphingosine 1-phosphate receptor 1] (S1P<sub>1</sub>), which has many structural similarities to LPA<sub>1</sub>. In fact, the transmembrane regions share a sequence identity of 41%. A defining difference between these two receptors is their mode of ligand access to the binding site. Where as the hydrophobic [https://en.wikipedia.org/wiki/Sphingosine-1-phosphate S1P ligand] enters S1P<sub>1</sub> via the membrane, LPA<sub>1</sub> has an extracellular opening that allows LPA access from the extracellular space. Structural evidence for this altered ligand pathway include global changes in the positioning of the extracellular loops (ECL) and transmembrane helices (TM). Specifically, this includes slight divergence of <scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene>, which is positioned 3 angstroms closer to TMVII compared to S1P<sub>1</sub>, and a repositioning of <scene name='72/721543/Ecl_regions/1'>ECL3</scene>, resulting in a divergence of 8 angstroms from S1P<sub>1</sub>. This narrowing of the gap between TMI and TMVII blocks membrane ligand access, while the greater distance between ECL3 and the other extracellular loops promotes extracellular access. Additionally, ECL0 is helical in S1P<sub>1</sub>, but lacks secondary structure in LPA<sub>1</sub>. This increased flexibility that results further promotes favorable access from the extracellular space.<br />
<br />
<scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene><br />
<br />
<scene name='72/721543/Ecl_regions/1'>ECL3</scene><br />
<br />
=== Endocannabinoid Receptor 1 ===<br />
LPA<sub>1</sub> also is closely related to the [http://www.nature.com/ijo/journal/v30/n1s/full/0803272a.html cannabinoid receptor] [https://en.wikipedia.org/wiki/Cannabinoid_receptor_type_1 CB1]. This close relation gives CB1 the ability to bind to analogs of LPA and vice versa, which opens the possibility of metabolic crosstalk between the two signaling systems. This connection is made possible through ligand phosphorylation and dephosphorylation. Specifically, complementary access to the LPA<sub>1</sub> binding pocket can be achieved by phosphorylated CB1 ligand analogs, while complementary access to the CB1 binding site required dephosphorylation of LPA<sub>1</sub> ligand analogs. In both cases, a ligand could serve as a primary receptor modulator and a simultaneous prodrug for a different receptor.<br />
<br />
<scene name='72/721543/Asp129_and_trp210/2'>TextToBeDisplayed</scene><br />
<br />
<br />
<br />
<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Chandler Mitchellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1172&diff=2584739Sandbox Reserved 11722016-03-29T13:36:18Z<p>Chandler Mitchell: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Central_Metabolism}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Lysophosphatidic Acid Receptor 1==<br />
<StructureSection load='4z34' size='340' side='right' caption='Cartoon representation of the LPA1 protein and its antagonist, ON7. ([https://en.wikipedia.org/wiki/Protein_Data_Bank PDB] code [http://www.rcsb.org/pdb/explore/explore.do?structureId=4z34 4Z34]) ' scene='72/721543/Overall/1'><br />
<br />
<br />
== Introduction ==<br />
[[Image:General_Picture.png |200 px|left|thumb| General image of the LPA<sub>1</sub> receptor's seven alpha helices]]<br />
Lysophosphatidic Acid Receptor 1 (commonly referred to as LPA<sub>1</sub>) is a [[G protein-coupled receptor]] and one of 6 different LPA receptors (LPA<sub>1</sub>-LPA<sub>6</sub>) that bind the phospholipid derivative [https://en.wikipedia.org/wiki/Lysophosphatidic_acid lysophosphatidic acid (LPA)], a signaling molecule that acts as a potent mitogen upon binding to one of its six receptors.<ref name="regpeps">PMID: 26091040</ref>, ----------- LPA<sub>1</sub> is part of the larger EDG receptor family(link) which includes the more widely known sphingosine 1-phopshate receptors.<br />
== Structure ==<br />
[[Image:ON7.png|200 px|left|thumb|LPA<sub>1</sub> receptor in tan, antagonist ON7 in green and red]]<br />
The LPA<sub>1</sub> receptor protein is composed of 364 amino acids with a mass of approximately 41 kDa. Just as other G-protein coupled receptors, LPA<sub>1</sub> contains seven alpha helices which make up the seven transmembrane spanning domains with three intracellular loops and three extracellular loops. Within these helices is an amphiphilic binding pocket enabling the LPA molecule to bind.<br />
=== Key Ligand Interactions ===<br />
Three separate interactions with an antagonist of LPA<sub>1</sub>, ON7, help demonstrate the key interactions that stabilize the binding of the LPA phospholipid to this receptor. At the polar region of the binding pocket, the majority of this region is stabilized by <scene name='72/721543/Arg124gln125/1'>Arg124 and Gln125</scene> forming ionic and polar interactions with the carboxylic acid and the hydroxyl group of ON7. In addition, interplay between <scene name='72/721543/Lys39_and_glu293/4'>Glu293 and Lys39</scene> causes another stabilizing component of the ON7 antagonist. Glu293 forms polar interactions with Lys39, positioning it in close proximity to to the carboxylic acid of ON7, which then interactions with Lys39 via ionic bonding. While Lys39 is highly conserved among all six LPA receptors, a His40 residue is present that is specific to the LPA<sub>1</sub> receptor. <scene name='72/721543/His40/1'>His40</scene> forms both ionic and polar interactions with the carboxylic acid of ON7. The protonation of this residue has been found to greatly affect the binding affinity of LPA, and is an important link to tumor growth and survival in acidic environments.<br />
<br />
<br />
== Function ==<br />
The LPA<sub>1</sub> receptor has been found to initiate downstream signaling cascades with three [https://en.wikipedia.org/wiki/G_protein G proteins] that signal for cell proliferation, survival, and migration. The LPA<sub>1</sub> receptor is present in nearly all cells and tissues throughout the body, and deletion of the LPA<sub>1</sub> receptor has been found to have physiological effects on every organ system. Despite this receptor being expressed throughout the body, LPA<sub>1</sub> has been found to be expressed highly in neural tissue, aiding in Schwann cell migration and myelination, formation of synapses, and glial cell growth. Recent studies have also found that the LPA<sub>1</sub> receptor is important in pain signal initiation via a [https://en.wikipedia.org/wiki/Rho-associated_protein_kinase ROCK] pathway.<br />
<br />
== Disease Relevance ==<br />
The LPA<sub>1</sub> receptor, depending on its level of expression, has been linked to both protective functions in the presence of a disease as well as causing a particular illness. For example, in patients with heart diseases, LPA<sub>1</sub> has been found to communicate with [[PI3K]], [https://en.wikipedia.org/wiki/Protein_kinase_B PKB], and [[ERK]] to induce a hypertrophic response in the heart in order to offset reduced heart contractions. In addition, due to LPA<sub>1</sub>'s function of pain signaling, overexertion of this protein can cause both [https://en.wikipedia.org/wiki/Allodynia allodynia] or [https://en.wikipedia.org/wiki/Hyperalgesia hyperalgesia], common symptoms of multiple sclerosis or a stroke.<br />
Because of the mitogen signaling activity of LPA<sub>1</sub>, abnormal expression or mutation of this receptor has been linked to tumor growth, survival, and migration in both liver and lung tumors. As recently discussed, the His40 on LPA<sub>1</sub>, when protonated, increased LPA binding affinity is increase by up to 1kcal/mol. Because of this, in an acidic environment that is typically produced by [https://en.wikipedia.org/wiki/Tumor_hypoxia hypoxic tumors] creating lactic acid, LPA<sub>1</sub> activity is increased, allowing these tumors to continue to proliferate, migrate, and survive. Lastly, due to the function of LPA<sub>1</sub> in myelinating Schwann cells, mutation of the receptor can also lead to a decrease in [https://en.wikipedia.org/wiki/Prepulse_inhibition prepulse inhibition], a general sign of schizophrenia.<br />
<br />
== Receptor Comparison ==<br />
<br />
=== Sphingosine 1-Phosphate Receptor ===<br />
LPA<sub>1</sub> belongs to the EDG (endothelial differentiation gene) family of [https://en.wikipedia.org/wiki/Lysophospholipid_receptor lysophospholipid receptors]. This family also includes the [https://en.wikipedia.org/wiki/S1PR1 sphingosine 1-phosphate receptor 1] (S1P<sub>1</sub>), which has many structural similarities to LPA<sub>1</sub>. In fact, the transmembrane regions share a sequence identity of 41%. A defining difference between these two receptors is their mode of ligand access to the binding site. Where as the hydrophobic [https://en.wikipedia.org/wiki/Sphingosine-1-phosphate S1P ligand] enters S1P<sub>1</sub> via the membrane, LPA<sub>1</sub> has an extracellular opening that allows LPA access from the extracellular space. Structural evidence for this altered ligand pathway include global changes in the positioning of the extracellular loops (ECL) and transmembrane helices (TM). Specifically, this includes slight divergence of <scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene>, which is positioned 3 angstroms closer to TMVII compared to S1P<sub>1</sub>, and a repositioning of <scene name='72/721543/Ecl_regions/1'>ECL3</scene>, resulting in a divergence of 8 angstroms from S1P<sub>1</sub>. This narrowing of the gap between TMI and TMVII blocks membrane ligand access, while the greater distance between ECL3 and the other extracellular loops promotes extracellular access. Additionally, ECL0 is helical in S1P<sub>1</sub>, but lacks secondary structure in LPA<sub>1</sub>. This increased flexibility that results further promotes favorable access from the extracellular space.<br />
<br />
<scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene><br />
<br />
<scene name='72/721543/Ecl_regions/1'>ECL3</scene><br />
<br />
=== Endocannabinoid Receptor 1 ===<br />
LPA<sub>1</sub> also is closely related to the [http://www.nature.com/ijo/journal/v30/n1s/full/0803272a.html cannabinoid receptor] [https://en.wikipedia.org/wiki/Cannabinoid_receptor_type_1 CB1]. This close relation gives CB1 the ability to bind to analogs of LPA and vice versa, which opens the possibility of metabolic crosstalk between the two signaling systems. This connection is made possible through ligand phosphorylation and dephosphorylation. Specifically, complementary access to the LPA<sub>1</sub> binding pocket can be achieved by phosphorylated CB1 ligand analogs, while complementary access to the CB1 binding site required dephosphorylation of LPA<sub>1</sub> ligand analogs.<br />
<br />
<scene name='72/721543/Asp129_and_trp210/2'>TextToBeDisplayed</scene><br />
<br />
<br />
<br />
<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Chandler Mitchellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1172&diff=2584715Sandbox Reserved 11722016-03-29T13:28:13Z<p>Chandler Mitchell: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Central_Metabolism}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Lysophosphatidic Acid Receptor 1==<br />
<StructureSection load='4z34' size='340' side='right' caption='Cartoon representation of the LPA1 protein and its antagonist, ON7. ([https://en.wikipedia.org/wiki/Protein_Data_Bank PDB] code [http://www.rcsb.org/pdb/explore/explore.do?structureId=4z34 4Z34]) ' scene='72/721543/Overall/1'><br />
<br />
<br />
== Introduction ==<br />
[[Image:General_Picture.png |200 px|left|thumb| General image of the LPA1 receptor's seven alpha helices]]<br />
Lysophosphatidic Acid Receptor 1 (commonly referred to as LPA1) is a [[G protein-coupled receptor]] and one of 6 different LPA receptors (LPA1-LPA6) that bind the phospholipid derivative [https://en.wikipedia.org/wiki/Lysophosphatidic_acid lysophosphatidic acid (LPA)], a signaling molecule that acts as a potent mitogen upon binding to one of its six receptors.<ref name="regpeps">PMID: 26091040</ref>, ----------- LPA1 is part of the larger EDG receptor family(link) which includes the more widely known sphingosine 1-phopshate receptors.<br />
== Structure ==<br />
[[Image:ON7.png|200 px|left|thumb|LPA<sub>1</sub> receptor in tan, antagonist ON7 in green and red]]<br />
The LPA<sub>1</sub> receptor protein is composed of 364 amino acids with a mass of approximately 41 kDa. Just as other G-protein coupled receptors, LPA<sub>1</sub> contains seven alpha helices which make up the seven transmembrane spanning domains with three intracellular loops and three extracellular loops. Within these helices is an amphiphilic binding pocket enabling the LPA molecule to bind.<br />
=== Key Ligand Interactions ===<br />
Three separate interactions with an antagonist of LPA<sub>1</sub>, ON7, help demonstrate the key interactions that stabilize the binding of the LPA phospholipid to this receptor. At the polar region of the binding pocket, the majority of this region is stabilized by <scene name='72/721543/Arg124gln125/1'>Arg124 and Gln125</scene> forming ionic and polar interactions with the carboxylic acid and the hydroxyl group of ON7. In addition, interplay between <scene name='72/721543/Lys39_and_glu293/4'>Glu293 and Lys39</scene> causes another stabilizing component of the ON7 antagonist. Glu293 forms polar interactions with Lys39, positioning it in close proximity to to the carboxylic acid of ON7, which then interactions with Lys39 via ionic bonding. While Lys39 is highly conserved among all six LPA receptors, a His40 residue is present that is specific to the LPA<sub>1</sub> receptor. <scene name='72/721543/His40/1'>His40</scene> forms both ionic and polar interactions with the carboxylic acid of ON7. The protonation of this residue has been found to greatly affect the binding affinity of LPA, and is an important link to tumor growth and survival in acidic environments.<br />
<br />
<br />
== Function ==<br />
The LPA<sub>1</sub> receptor has been found to initiate downstream signaling cascades with three [https://en.wikipedia.org/wiki/G_protein G proteins] that signal for cell proliferation, survival, and migration. The LPA<sub>1</sub> receptor is present in nearly all cells and tissues throughout the body, and deletion of the LPA<sub>1</sub> receptor has been found to have physiological effects on every organ system. Despite this receptor being expressed throughout the body, LPA<sub>1</sub> has been found to be expressed highly in neural tissue, aiding in Schwann cell migration and myelination, formation of synapses, and glial cell growth. Recent studies have also found that the LPA<sub>1</sub> receptor is important in pain signal initiation via a [https://en.wikipedia.org/wiki/Rho-associated_protein_kinase ROCK] pathway.<br />
<br />
== Disease Relevance ==<br />
The LPA<sub>1</sub> receptor, depending on its level of expression, has been linked to both protective functions in the presence of a disease as well as causing a particular illness. For example, in patients with heart diseases, LPA<sub>1</sub> has been found to communicate with [[PI3K]], [https://en.wikipedia.org/wiki/Protein_kinase_B PKB], and [[ERK]] to induce a hypertrophic response in the heart in order to offset reduced heart contractions. In addition, due to LPA<sub>1</sub>'s function of pain signaling, overexertion of this protein can cause both [https://en.wikipedia.org/wiki/Allodynia allodynia] or [https://en.wikipedia.org/wiki/Hyperalgesia hyperalgesia], common symptoms of multiple sclerosis or a stroke.<br />
Because of the mitogen signaling activity of LPA<sub>1</sub>, abnormal expression or mutation of this receptor has been linked to tumor growth, survival, and migration in both liver and lung tumors. As recently discussed, the His40 on LPA<sub>1</sub>, when protonated, increased LPA binding affinity is increase by up to 1kcal/mol. Because of this, in an acidic environment that is typically produced by [https://en.wikipedia.org/wiki/Tumor_hypoxia hypoxic tumors] creating lactic acid, LPA<sub>1</sub> activity is increased, allowing these tumors to continue to proliferate, migrate, and survive. Lastly, due to the function of LPA<sub>1</sub> in myelinating Schwann cells, mutation of the receptor can also lead to a decrease in [https://en.wikipedia.org/wiki/Prepulse_inhibition prepulse inhibition], a general sign of schizophrenia.<br />
<br />
== Receptor Comparison ==<br />
<br />
=== Sphingosine 1-Phosphate Receptor ===<br />
LPA<sub>1</sub> belongs to the EDG (endothelial differentiation gene) family of [https://en.wikipedia.org/wiki/Lysophospholipid_receptor lysophospholipid receptors]. This family also includes the [https://en.wikipedia.org/wiki/S1PR1 sphingosine 1-phosphate receptor 1] (S1P<sub>1</sub>), which has many structural similarities to LPA<sub>1</sub>. In fact, the transmembrane regions share a sequence identity of 41%. A defining difference between these two receptors is their mode of ligand access to the binding site. Where as the hydrophobic [https://en.wikipedia.org/wiki/Sphingosine-1-phosphate S1P ligand] enters S1P<sub>1</sub> via the membrane, LPA<sub>1</sub> has an extracellular opening that allows LPA access from the extracellular space. Structural evidence for this altered ligand pathway include global changes in the positioning of the extracellular loops (ECL) and transmembrane helices (TM). Specifically, this includes slight divergence of <scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene>, which is positioned 3 angstroms closer to TMVII compared to S1P<sub>1</sub>, and a repositioning of <scene name='72/721543/Ecl_regions/1'>ECL3</scene>, resulting in a divergence of 8 angstroms from S1P<sub>1</sub>. This narrowing of the gap between TMI and TMVII blocks membrane ligand access, while the greater distance between ECL3 and the other extracellular loops promotes extracellular access. Additionally, ECL0 is helical in S1P<sub>1</sub>, but lacks secondary structure in LPA<sub>1</sub>. This increased flexibility that results further promotes favorable access from the extracellular space.<br />
<br />
<scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene><br />
<br />
<scene name='72/721543/Ecl_regions/1'>ECL3</scene><br />
<br />
=== Endocannabinoid Receptor 1 ===<br />
LPA<sub>1</sub> also is closely related to the [http://www.nature.com/ijo/journal/v30/n1s/full/0803272a.html cannabinoid receptor] [https://en.wikipedia.org/wiki/Cannabinoid_receptor_type_1 CB1]. This close relation gives CB1 the ability to bind to analogs of LPA and vice versa, which opens the possibility of metabolic crosstalk between the two signaling systems. This connection is made possible through ligand phosphorylation and dephosphorylation. Specifically, complementary access to the LPA<sub>1</sub> binding pocket can be achieved by phosphorylated CB1 ligand analogs, while complementary access to the CB1 binding site required dephosphorylation of LPA<sub>1</sub> ligand analogs.<br />
<br />
<scene name='72/721543/Asp129_and_trp210/2'>TextToBeDisplayed</scene><br />
<br />
<br />
<br />
<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Chandler Mitchellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1172&diff=2584688Sandbox Reserved 11722016-03-29T13:18:16Z<p>Chandler Mitchell: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Central_Metabolism}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Lysophosphatidic Acid Receptor 1==<br />
<StructureSection load='4z34' size='340' side='right' caption='Cartoon representation of the LPA<sub>1</sub> protein and its antagonist, ON7. ([https://en.wikipedia.org/wiki/Protein_Data_Bank PDB] code [http://www.rcsb.org/pdb/explore/explore.do?structureId=4z34 4Z34]) ' scene='72/721543/Overall/1'><br />
<br />
<br />
== Introduction ==<br />
[[Image:General_Picture.png |200 px|left|thumb| General image of the LPA1 receptor's seven alpha helices]]<br />
Lysophosphatidic Acid Receptor 1 (commonly referred to as LPA1) is a [[G protein-coupled receptor]] and one of 6 different LPA receptors (LPA1-LPA6) that bind the phospholipid derivative [https://en.wikipedia.org/wiki/Lysophosphatidic_acid lysophosphatidic acid (LPA)], a signaling molecule that acts as a potent mitogen upon binding to one of its six receptors.<ref name="regpeps">PMID: 26091040</ref>, ----------- LPA1 is part of the larger EDG receptor family(link) which includes the more widely known sphingosine 1-phopshate receptors.<br />
== Structure ==<br />
[[Image:ON7.png|200 px|left|thumb|LPA1 receptor in tan, antagonist ON7 in green and red]]<br />
The LPA<sub>1</sub> receptor protein is composed of 364 amino acids with a mass of approximately 41 kDa. Just as other G-protein coupled receptors, LPA1 contains seven alpha helices which make up the seven transmembrane spanning domains with three intracellular loops and three extracellular loops. Within these helices is an amphiphilic binding pocket enabling the LPA molecule to bind.<br />
=== Key Ligand Interactions ===<br />
Three separate interactions with an antagonist of LPA1, ON7, help demonstrate the key interactions that stabilize the binding of the LPA phospholipid to this receptor. At the polar region of the binding pocket, the majority of this region is stabilized by <scene name='72/721543/Arg124gln125/1'>Arg124 and Gln125</scene> forming ionic and polar interactions with the carboxylic acid and the hydroxyl group of ON7. In addition, interplay between <scene name='72/721543/Lys39_and_glu293/4'>Glu293 and Lys39</scene> causes another stabilizing component of the ON7 antagonist. Glu293 forms polar interactions with Lys39, positioning it in close proximity to to the carboxylic acid of ON7, which then interactions with Lys39 via ionic bonding. While Lys39 is highly conserved among all six LPA receptors, a His40 residue is present that is specific to the LPA1 receptor. <scene name='72/721543/His40/1'>His40</scene> forms both ionic and polar interactions with the carboxylic acid of ON7. The protonation of this residue has been found to greatly affect the binding affinity of LPA, and is an important link to tumor growth and survival in acidic environments.<br />
<br />
<br />
== Function ==<br />
The LPA1 receptor has been found to initiate downstream signaling cascades with three [https://en.wikipedia.org/wiki/G_protein G proteins] that signal for cell proliferation, survival, and migration. The LPA1 receptor is present in nearly all cells and tissues throughout the body, and deletion of the LPA1 receptor has been found to have physiological effects on every organ system. Despite this receptor being expressed throughout the body, LPA1 has been found to be expressed highly in neural tissue, aiding in Schwann cell migration and myelination, formation of synapses, and glial cell growth. Recent studies have also found that the LPA1 receptor is important in pain signal initiation via a [https://en.wikipedia.org/wiki/Rho-associated_protein_kinase ROCK] pathway.<br />
<br />
== Disease Relevance ==<br />
The LPA1 receptor, depending on its level of expression, has been linked to both protective functions in the presence of a disease as well as causing a particular illness. For example, in patients with heart diseases, LPA1 has been found to communicate with [[PI3K]], [https://en.wikipedia.org/wiki/Protein_kinase_B PKB], and [[ERK]] to induce a hypertrophic response in the heart in order to offset reduced heart contractions. In addition, due to LPA1's function of pain signaling, overexertion of this protein can cause both [https://en.wikipedia.org/wiki/Allodynia allodynia] or [https://en.wikipedia.org/wiki/Hyperalgesia hyperalgesia], common symptoms of multiple sclerosis or a stroke.<br />
Because of the mitogen signaling activity of LPA1, abnormal expression or mutation of this receptor has been linked to tumor growth, survival, and migration in both liver and lung tumors. As recently discussed, the His40 on LPA1, when protonated, increased LPA binding affinity is increase by up to 1kcal/mol. Because of this, in an acidic environment that is typically produced by [https://en.wikipedia.org/wiki/Tumor_hypoxia hypoxic tumors] creating lactic acid, LPA1 activity is increased, allowing these tumors to continue to proliferate, migrate, and survive. Lastly, due to the function of LPA1 in myelinating Schwann cells, mutation of the receptor can also lead to a decrease in [https://en.wikipedia.org/wiki/Prepulse_inhibition prepulse inhibition], a general sign of schizophrenia.<br />
<br />
== Receptor Comparison ==<br />
<br />
=== Sphingosine 1-Phosphate Receptor ===<br />
LPA1 belongs to the EDG (endothelial differentiation gene) family of [https://en.wikipedia.org/wiki/Lysophospholipid_receptor lysophospholipid receptors]. This family also includes the [https://en.wikipedia.org/wiki/S1PR1 sphingosine 1-phosphate receptor 1] (S1P1), which has many structural similarities to LPA1. In fact, the transmembrane regions share a sequence identity of 41%. A defining difference between these two receptors their mode of ligand access to the binding site. Where as the hydrophobic [https://en.wikipedia.org/wiki/Sphingosine-1-phosphate S1P ligand] enters S1P1 via the membrane, LPA1 has an extracellular opening that allows LPA access from the extracellular space. Structural evidence for this altered ligand pathway include global changes in the positioning of the extracellular loops (ECL) and transmembrane helices (TM). Specifically, this includes slight divergence of <scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene>, which is positioned 3 angstroms closer to TMVII compared to S1P1, and a repositioning of <scene name='72/721543/Ecl_regions/1'>ECL3</scene>, resulting in a divergence of 8 angstroms from S1P1. This narrowing of the gap between TMI and TMVII blocks membrane ligand access, while the greater distance between ECL3 and the other extracellular loops promotes extracellular access. Additionally, ECL0 is helical in S1P1, but lacks secondary structure in LPA1. This increased flexibility that results further promotes favorable access from the extracellular space.<br />
<br />
<scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene><br />
<br />
<scene name='72/721543/Ecl_regions/1'>ECL3</scene><br />
<br />
=== Endocannabinoid Receptor 1 ===<br />
LPA1 also is closely related to the [http://www.nature.com/ijo/journal/v30/n1s/full/0803272a.html cannabinoid receptor] [https://en.wikipedia.org/wiki/Cannabinoid_receptor_type_1 CB1]. This close relation gives CB1 the ability to bind to analogs of LPA and vice versa, which opens the possibility of metabolic crosstalk between the two signaling systems. This connection is made possible through ligand phosphorylation and dephosphorylation. Specifically, complementary access to the LPA1 binding pocket can be achieved by phosphorylated CB1 ligand analogs, while complementary access to the CB1 binding site required dephosphorylation of LPA1 ligand analogs.<br />
<br />
<scene name='72/721543/Asp129_and_trp210/2'>TextToBeDisplayed</scene><br />
<br />
<br />
<br />
<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Chandler Mitchellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1172&diff=2584674Sandbox Reserved 11722016-03-29T13:14:46Z<p>Chandler Mitchell: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Central_Metabolism}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Lysophosphatidic Acid Receptor 1==<br />
<StructureSection load='4z34' size='340' side='right' caption='Cartoon representation of the LPA1 protein and its antagonist, ON7. ([https://en.wikipedia.org/wiki/Protein_Data_Bank PDB] code [http://www.rcsb.org/pdb/explore/explore.do?structureId=4z34 4Z34]) ' scene='72/721543/Overall/1'><br />
<br />
<br />
== Introduction ==<br />
[[Image:General_Picture.png |200 px|left|thumb| General image of the LPA1 receptor's seven alpha helices]]<br />
Lysophosphatidic Acid Receptor 1 (commonly referred to as LPA1) is a [[G protein-coupled receptor]] and one of 6 different LPA receptors (LPA1-LPA6) that bind the phospholipid derivative [https://en.wikipedia.org/wiki/Lysophosphatidic_acid lysophosphatidic acid (LPA)], a signaling molecule that acts as a potent mitogen upon binding to one of its six receptors.<ref name="regpeps">PMID: 26091040</ref>, ----------- LPA1 is part of the larger EDG receptor family(link) which includes the more widely known sphingosine 1-phopshate receptors.<br />
== Structure ==<br />
[[Image:ON7.png|200 px|left|thumb|LPA1 receptor in tan, antagonist ON7 in green and red]]<br />
The LPA<sub>1</sub> receptor protein is composed of 364 amino acids with a mass of approximately 41 kDa. Just as other G-protein coupled receptors, LPA1 contains seven alpha helices which make up the seven transmembrane spanning domains with three intracellular loops and three extracellular loops. Within these helices is an amphiphilic binding pocket enabling the LPA molecule to bind.<br />
=== Key Ligand Interactions ===<br />
Three separate interactions with an antagonist of LPA1, ON7, help demonstrate the key interactions that stabilize the binding of the LPA phospholipid to this receptor. At the polar region of the binding pocket, the majority of this region is stabilized by <scene name='72/721543/Arg124gln125/1'>Arg124 and Gln125</scene> forming ionic and polar interactions with the carboxylic acid and the hydroxyl group of ON7. In addition, interplay between <scene name='72/721543/Lys39_and_glu293/4'>Glu293 and Lys39</scene> causes another stabilizing component of the ON7 antagonist. Glu293 forms polar interactions with Lys39, positioning it in close proximity to to the carboxylic acid of ON7, which then interactions with Lys39 via ionic bonding. While Lys39 is highly conserved among all six LPA receptors, a His40 residue is present that is specific to the LPA1 receptor. <scene name='72/721543/His40/1'>His40</scene> forms both ionic and polar interactions with the carboxylic acid of ON7. The protonation of this residue has been found to greatly affect the binding affinity of LPA, and is an important link to tumor growth and survival in acidic environments.<br />
<br />
<br />
== Function ==<br />
The LPA1 receptor has been found to initiate downstream signaling cascades with three [https://en.wikipedia.org/wiki/G_protein G proteins] that signal for cell proliferation, survival, and migration. The LPA1 receptor is present in nearly all cells and tissues throughout the body, and deletion of the LPA1 receptor has been found to have physiological effects on every organ system. Despite this receptor being expressed throughout the body, LPA1 has been found to be expressed highly in neural tissue, aiding in Schwann cell migration and myelination, formation of synapses, and glial cell growth. Recent studies have also found that the LPA1 receptor is important in pain signal initiation via a [https://en.wikipedia.org/wiki/Rho-associated_protein_kinase ROCK] pathway.<br />
<br />
== Disease Relevance ==<br />
The LPA1 receptor, depending on its level of expression, has been linked to both protective functions in the presence of a disease as well as causing a particular illness. For example, in patients with heart diseases, LPA1 has been found to communicate with [[PI3K]], [https://en.wikipedia.org/wiki/Protein_kinase_B PKB], and [[ERK]] to induce a hypertrophic response in the heart in order to offset reduced heart contractions. In addition, due to LPA1's function of pain signaling, overexertion of this protein can cause both [https://en.wikipedia.org/wiki/Allodynia allodynia] or [https://en.wikipedia.org/wiki/Hyperalgesia hyperalgesia], common symptoms of multiple sclerosis or a stroke.<br />
Because of the mitogen signaling activity of LPA1, abnormal expression or mutation of this receptor has been linked to tumor growth, survival, and migration in both liver and lung tumors. As recently discussed, the His40 on LPA1, when protonated, increased LPA binding affinity is increase by up to 1kcal/mol. Because of this, in an acidic environment that is typically produced by [https://en.wikipedia.org/wiki/Tumor_hypoxia hypoxic tumors] creating lactic acid, LPA1 activity is increased, allowing these tumors to continue to proliferate, migrate, and survive. Lastly, due to the function of LPA1 in myelinating Schwann cells, mutation of the receptor can also lead to a decrease in [https://en.wikipedia.org/wiki/Prepulse_inhibition prepulse inhibition], a general sign of schizophrenia.<br />
<br />
== Receptor Comparison ==<br />
<br />
=== Sphingosine 1-Phosphate Receptor ===<br />
LPA1 belongs to the EDG (endothelial differentiation gene) family of [https://en.wikipedia.org/wiki/Lysophospholipid_receptor lysophospholipid receptors]. This family also includes the [https://en.wikipedia.org/wiki/S1PR1 sphingosine 1-phosphate receptor 1] (S1P1), which has many structural similarities to LPA1. In fact, the transmembrane regions share a sequence identity of 41%. A defining difference between these two receptors their mode of ligand access to the binding site. Where as the hydrophobic [https://en.wikipedia.org/wiki/Sphingosine-1-phosphate S1P ligand] enters S1P1 via the membrane, LPA1 has an extracellular opening that allows LPA access from the extracellular space. Structural evidence for this altered ligand pathway include global changes in the positioning of the extracellular loops (ECL) and transmembrane helices (TM). Specifically, this includes slight divergence of <scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene>, which is positioned 3 angstroms closer to TMVII compared to S1P1, and a repositioning of <scene name='72/721543/Ecl_regions/1'>ECL3</scene>, resulting in a divergence of 8 angstroms from S1P1. This narrowing of the gap between TMI and TMVII blocks membrane ligand access, while the greater distance between ECL3 and the other extracellular loops promotes extracellular access. Additionally, ECL0 is helical in S1P1, but lacks secondary structure in LPA1. This increased flexibility that results further promotes favorable access from the extracellular space.<br />
<br />
<scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene><br />
<br />
<scene name='72/721543/Ecl_regions/1'>ECL3</scene><br />
<br />
=== Endocannabinoid Receptor 1 ===<br />
LPA1 also is closely related to the [http://www.nature.com/ijo/journal/v30/n1s/full/0803272a.html cannabinoid receptor] [https://en.wikipedia.org/wiki/Cannabinoid_receptor_type_1 CB1]. This close relation gives CB1 the ability to bind to analogs of LPA and vice versa, which opens the possibility of metabolic crosstalk between the two signaling systems. This connection is made possible through ligand phosphorylation and dephosphorylation. Specifically, complementary access to the LPA1 binding pocket can be achieved by phosphorylated CB1 ligand analogs, while complementary access to the CB1 binding site required dephosphorylation of LPA1 ligand analogs.<br />
<br />
<scene name='72/721543/Asp129_and_trp210/2'>TextToBeDisplayed</scene><br />
<br />
<br />
<br />
<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Chandler Mitchellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1172&diff=2584661Sandbox Reserved 11722016-03-29T13:09:45Z<p>Chandler Mitchell: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Central_Metabolism}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Lysophosphatidic Acid Receptor 1==<br />
<StructureSection load='4z34' size='340' side='right' caption='Cartoon representation of the LPA1 protein and its antagonist, ON7. ([https://en.wikipedia.org/wiki/Protein_Data_Bank PDB] code [http://www.rcsb.org/pdb/explore/explore.do?structureId=4z34 4Z34]) ' scene=''><br />
<br />
<br />
== Introduction ==<br />
[[Image:General_Picture.png |200 px|left|thumb| General image of the LPA1 receptor's seven alpha helices]]<br />
Lysophosphatidic Acid Receptor 1 (commonly referred to as LPA1) is a [[G protein-coupled receptor]] and one of 6 different LPA receptors (LPA1-LPA6) that bind the phospholipid derivative [https://en.wikipedia.org/wiki/Lysophosphatidic_acid lysophosphatidic acid (LPA)], a signaling molecule that acts as a potent mitogen upon binding to one of its six receptors.<ref name="regpeps">PMID: 26091040</ref>, ----------- LPA1 is part of the larger EDG receptor family(link) which includes the more widely known sphingosine 1-phopshate receptors.<br />
== Structure ==<br />
[[Image:ON7.png|200 px|left|thumb|LPA1 receptor in tan, antagonist ON7 in green and red]]<br />
The LPA1 receptor protein is composed of 364 amino acids with a mass of approximately 41 kDa. Just as other G-protein coupled receptors, LPA1 contains seven alpha helices which make up the seven transmembrane spanning domains with three intracellular loops and three extracellular loops. Within these helices is an amphiphilic binding pocket enabling the LPA molecule to bind.<br />
=== Key Ligand Interactions ===<br />
Three separate interactions with an antagonist of LPA1, ON7, help demonstrate the key interactions that stabilize the binding of the LPA phospholipid to this receptor. At the polar region of the binding pocket, the majority of this region is stabilized by <scene name='72/721543/Arg124gln125/1'>Arg124 and Gln125</scene> forming ionic and polar interactions with the carboxylic acid and the hydroxyl group of ON7. In addition, interplay between <scene name='72/721543/Lys39_and_glu293/4'>Glu293 and Lys39</scene> causes another stabilizing component of the ON7 antagonist. Glu293 forms polar interactions with Lys39, positioning it in close proximity to to the carboxylic acid of ON7, which then interactions with Lys39 via ionic bonding. While Lys39 is highly conserved among all six LPA receptors, a His40 residue is present that is specific to the LPA1 receptor. <scene name='72/721543/His40/1'>His40</scene> forms both ionic and polar interactions with the carboxylic acid of ON7. The protonation of this residue has been found to greatly affect the binding affinity of LPA, and is an important link to tumor growth and survival in acidic environments.<br />
<br />
<br />
== Function ==<br />
The LPA1 receptor has been found to initiate downstream signaling cascades with three [https://en.wikipedia.org/wiki/G_protein G proteins] that signal for cell proliferation, survival, and migration. The LPA1 receptor is present in nearly all cells and tissues throughout the body, and deletion of the LPA1 receptor has been found to have physiological effects on every organ system. Despite this receptor being expressed throughout the body, LPA1 has been found to be expressed highly in neural tissue, aiding in Schwann cell migration and myelination, formation of synapses, and glial cell growth. Recent studies have also found that the LPA1 receptor is important in pain signal initiation via a [https://en.wikipedia.org/wiki/Rho-associated_protein_kinase ROCK] pathway.<br />
<br />
== Disease Relevance ==<br />
The LPA1 receptor, depending on its level of expression, has been linked to both protective functions in the presence of a disease as well as causing a particular illness. For example, in patients with heart diseases, LPA1 has been found to communicate with [[PI3K]], [https://en.wikipedia.org/wiki/Protein_kinase_B PKB], and [[ERK]] to induce a hypertrophic response in the heart in order to offset reduced heart contractions. In addition, due to LPA1's function of pain signaling, overexertion of this protein can cause both [https://en.wikipedia.org/wiki/Allodynia allodynia] or [https://en.wikipedia.org/wiki/Hyperalgesia hyperalgesia], common symptoms of multiple sclerosis or a stroke.<br />
Because of the mitogen signaling activity of LPA1, abnormal expression or mutation of this receptor has been linked to tumor growth, survival, and migration in both liver and lung tumors. As recently discussed, the His40 on LPA1, when protonated, increased LPA binding affinity is increase by up to 1kcal/mol. Because of this, in an acidic environment that is typically produced by [https://en.wikipedia.org/wiki/Tumor_hypoxia hypoxic tumors] creating lactic acid, LPA1 activity is increased, allowing these tumors to continue to proliferate, migrate, and survive. Lastly, due to the function of LPA1 in myelinating Schwann cells, mutation of the receptor can also lead to a decrease in [https://en.wikipedia.org/wiki/Prepulse_inhibition prepulse inhibition], a general sign of schizophrenia.<br />
<br />
== Receptor Comparison ==<br />
<br />
=== Sphingosine 1-Phosphate Receptor ===<br />
LPA1 belongs to the EDG (endothelial differentiation gene) family of [https://en.wikipedia.org/wiki/Lysophospholipid_receptor lysophospholipid receptors]. This family also includes the [https://en.wikipedia.org/wiki/S1PR1 sphingosine 1-phosphate receptor 1] (S1P1), which has many structural similarities to LPA1. In fact, the transmembrane regions share a sequence identity of 41%. A defining difference between these two receptors their mode of ligand access to the binding site. Where as the hydrophobic [https://en.wikipedia.org/wiki/Sphingosine-1-phosphate S1P ligand] enters S1P1 via the membrane, LPA1 has an extracellular opening that allows LPA access from the extracellular space. Structural evidence for this altered ligand pathway include global changes in the positioning of the extracellular loops (ECL) and transmembrane helices (TM). Specifically, this includes slight divergence of <scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene>, which is positioned 3 angstroms closer to TMVII compared to S1P1, and a repositioning of <scene name='72/721543/Ecl_regions/1'>ECL3</scene>, resulting in a divergence of 8 angstroms from S1P1. This narrowing of the gap between TMI and TMVII blocks membrane ligand access, while the greater distance between ECL3 and the other extracellular loops promotes extracellular access. Additionally, ECL0 is helical in S1P1, but lacks secondary structure in LPA1. This increased flexibility that results further promotes favorable access from the extracellular space.<br />
<br />
<scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene><br />
<br />
<scene name='72/721543/Ecl_regions/1'>ECL3</scene><br />
<br />
=== Endocannabinoid Receptor 1 ===<br />
LPA1 also is closely related to the [http://www.nature.com/ijo/journal/v30/n1s/full/0803272a.html cannabinoid receptor] [https://en.wikipedia.org/wiki/Cannabinoid_receptor_type_1 CB1]. This close relation gives CB1 the ability to bind to analogs of LPA and vice versa, which opens the possibility of metabolic crosstalk between the two signaling systems. This connection is made possible through ligand phosphorylation and dephosphorylation. Specifically, complementary access to the LPA1 binding pocket can be achieved by phosphorylated CB1 ligand analogs, while complementary access to the CB1 binding site required dephosphorylation of LPA1 ligand analogs.<br />
<br />
<scene name='72/721543/Asp129_and_trp210/2'>TextToBeDisplayed</scene><br />
<br />
<br />
<br />
<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Chandler Mitchellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1172&diff=2584639Sandbox Reserved 11722016-03-29T12:56:29Z<p>Chandler Mitchell: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Central_Metabolism}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Lysophosphatidic Acid Receptor 1==<br />
<StructureSection load='4z34' size='340' side='right' caption='Cartoon representation of the LPA1 protein and its antagonist, ON7. ([https://en.wikipedia.org/wiki/Protein_Data_Bank PDB] code [http://www.rcsb.org/pdb/explore/explore.do?structureId=4z34 4Z34]) ' scene=''><br />
<br />
<br />
== Introduction ==<br />
[[Image:General_Picture.png |200 px|left|thumb| General image of the LPA1 receptor's seven alpha helices]]<br />
Lysophosphatidic Acid Receptor 1 (commonly referred to as LPA1) is a [[G protein-coupled receptor]] and one of 6 different LPA receptors (LPA1-LPA6) that bind the phospholipid derivative [https://en.wikipedia.org/wiki/Lysophosphatidic_acid lysophosphatidic acid (LPA)], a signaling molecule that acts as a potent mitogen upon binding to one of its six receptors.<ref name="regpeps">PMID: 26091040</ref>, ----------- LPA1 is part of the larger EDG receptor family(link) which includes the more widely known sphingosine 1-phopshate receptors.<br />
== Structure ==<br />
[[Image:ON7.png|200 px|left|thumb|LPA1 receptor in tan, antagonist ON7 in green and red]]<br />
The LPA1 receptor protein is composed of 364 amino acids with a mass of approximately 41 kDa. Just as other G-protein coupled receptors, LPA1 contains seven alpha helices which make up the seven transmembrane spanning domains with three intracellular loops and three extracellular loops. Within these helices is an amphiphilic binding pocket enabling the LPA molecule to bind.<br />
=== Key Ligand Interactions ===<br />
Three separate interactions with an antagonist of LPA1, ON7, help demonstrate the key interactions that stabilize the binding of the LPA phospholipid to this receptor. At the polar region of the binding pocket, the majority of this region is stabilized by <scene name='72/721543/Arg124gln125/1'>Arg124 and Gln125</scene> forming ionic and polar interactions with the carboxylic acid and the hydroxyl group of ON7. In addition, interplay between <scene name='72/721543/Lys39_and_glu293/4'>Glu293 and Lys39</scene> causes another stabilizing component of the ON7 antagonist. Glu293 forms polar interactions with Lys39, positioning it in close proximity to to the carboxylic acid of ON7, which then interactions with Lys39 via ionic bonding. While Lys39 is highly conserved among all six LPA receptors, a His40 residue is present that is specific to the LPA1 receptor. <scene name='72/721543/His40/1'>His40</scene> forms both ionic and polar interactions with the carboxylic acid of ON7. The protonation of this residue has been found to greatly affect the binding affinity of LPA, and is an important link to tumor growth and survival in acidic environments.<br />
<br />
<br />
== Function ==<br />
The LPA1 receptor has been found to initiate downstream signaling cascades with three [https://en.wikipedia.org/wiki/G_protein G proteins] that signal for cell proliferation, survival, and migration. The LPA1 receptor is present in nearly all cells and tissues throughout the body, and deletion of the LPA1 receptor has been found to have physiological effects on every organ system. Despite this receptor being expressed throughout the body, LPA1 has been found to be expressed highly in neural tissue, aiding in Schwann cell migration and myelination, formation of synapses, and glial cell growth. Recent studies have also found that the LPA1 receptor is important in pain signal initiation via a [https://en.wikipedia.org/wiki/Rho-associated_protein_kinase ROCK] pathway.<br />
<br />
== Disease Relevance ==<br />
The LPA1 receptor, depending on its level of expression, has been linked to both protective functions in the presence of a disease as well as causing a particular illness. For example, in patients with heart diseases, LPA1 has been found to communicate with [[PI3K]], [https://en.wikipedia.org/wiki/Protein_kinase_B PKB], and [[ERK]] to induce a hypertrophic response in the heart in order to offset reduced heart contractions. In addition, due to LPA1's function of pain signaling, overexertion of this protein can cause both [https://en.wikipedia.org/wiki/Allodynia allodynia] or [https://en.wikipedia.org/wiki/Hyperalgesia hyperalgesia], common symptoms of multiple sclerosis or a stroke.<br />
Because of the mitogen signaling activity of LPA1, abnormal expression or mutation of this receptor has been linked to tumor growth, survival, and migration in both liver and lung tumors. As recently discussed, the His40 on LPA1, when protonated, increased LPA binding affinity is increase by up to 1kcal/mol. Because of this, in an acidic environment that is typically produced by [https://en.wikipedia.org/wiki/Tumor_hypoxia hypoxic tumors] creating lactic acid, LPA1 activity is increased, allowing these tumors to continue to proliferate, migrate, and survive. Lastly, due to the function of LPA1 in myelinating Schwann cells, mutation of the receptor can also lead to a decrease in [https://en.wikipedia.org/wiki/Prepulse_inhibition prepulse inhibition], a general sign of schizophrenia.<br />
<br />
== Receptor Comparison ==<br />
<br />
=== Sphingosine 1-Phosphate Receptor ===<br />
LPA1 belongs to the EDG (endothelial differentiation gene) family of [https://en.wikipedia.org/wiki/Lysophospholipid_receptor lysophospholipid receptors]. This family also includes the [https://en.wikipedia.org/wiki/S1PR1 sphingosine 1-phosphate receptor 1] (S1P1), which has many structural similarities to LPA1. In fact, the transmembrane regions share a sequence identity of 41%. A defining difference between these two receptors their mode of ligand access to the binding site. Where as the hydrophobic [https://en.wikipedia.org/wiki/Sphingosine-1-phosphate S1P ligand] enters S1P1 via the membrane, LPA1 has an extracellular opening that allows LPA access from the extracellular space. Structural evidence for this altered ligand pathway include global changes in the positioning of the extracellular loops (ECL) and transmembrane helices (TM). Specifically, this includes slight divergence of <scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene>, which is positioned 3 angstroms closer to TMVII compared to S1P1, and a repositioning of <scene name='72/721543/Ecl_regions/1'>ECL3</scene>, resulting in a divergence of 8 angstroms from S1P1. This narrowing of the gap between TMI and TMVII blocks membrane ligand access, while the greater distance between ECL3 and the other extracellular loops promotes extracellular access. Additionally, ECL0 is helical in S1P1, but lacks secondary structure in LPA1. This increased flexibility that results further promotes favorable access from the extracellular space.<br />
<br />
<scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene><br />
<br />
<scene name='72/721543/Ecl_regions/1'>ECL3</scene><br />
<br />
=== Endocannabinoid Receptor 1 ===<br />
LPA1 also is closely related to the [http://www.nature.com/ijo/journal/v30/n1s/full/0803272a.html cannabinoid receptor] [https://en.wikipedia.org/wiki/Cannabinoid_receptor_type_1 CB1]. This close relation gives CB1 the ability to bind to analogs of LPA and vice versa, which opens the possibility of metabolic crosstalk between the two signaling systems.<br />
<br />
<scene name='72/721543/Asp129_and_trp210/2'>TextToBeDisplayed</scene><br />
<br />
<br />
<br />
<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Chandler Mitchellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1172&diff=2584604Sandbox Reserved 11722016-03-29T12:36:12Z<p>Chandler Mitchell: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Central_Metabolism}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Lysophosphatidic Acid Receptor 1==<br />
<StructureSection load='4z34' size='340' side='right' caption='Cartoon representation of the LPA1 protein and its antagonist, ON7. ([https://en.wikipedia.org/wiki/Protein_Data_Bank PDB] code [http://www.rcsb.org/pdb/explore/explore.do?structureId=4z34 4Z34]) ' scene=''><br />
<br />
<br />
== Introduction ==<br />
[[Image:General_Picture.png |200 px|left|thumb| General image of the LPA1 receptor's seven alpha helices]]<br />
Lysophosphatidic Acid Receptor 1 (commonly referred to as LPA1) is a [[G protein-coupled receptor]] and one of 6 different LPA receptors (LPA1-LPA6) that bind the phospholipid derivative [https://en.wikipedia.org/wiki/Lysophosphatidic_acid lysophosphatidic acid (LPA)], a signaling molecule that acts as a potent mitogen upon binding to one of its six receptors.<ref name="regpeps">PMID: 26091040</ref>, ----------- LPA1 is part of the larger EDG receptor family(link) which includes the more widely known sphingosine 1-phopshate receptors.<br />
== Structure ==<br />
[[Image:ON7.png|200 px|left|thumb|LPA1 receptor in tan, antagonist ON7 in green and red]]<br />
The LPA1 receptor protein is composed of 364 amino acids with a mass of approximately 41 kDa. Just as other G-protein coupled receptors, LPA1 contains seven alpha helices which make up the seven transmembrane spanning domains with three intracellular loops and three extracellular loops. Within these helices is an amphiphilic binding pocket enabling the LPA molecule to bind.<br />
=== Key Ligand Interactions ===<br />
Three separate interactions with an antagonist of LPA1, ON7, help demonstrate the key interactions that stabilize the binding of the LPA phospholipid to this receptor. At the polar region of the binding pocket, the majority of this region is stabilized by <scene name='72/721543/Arg124gln125/1'>Arg124 and Gln125</scene> forming ionic and polar interactions with the carboxylic acid and the hydroxyl group of ON7. In addition, interplay between <scene name='72/721543/Lys39_and_glu293/4'>Glu293 and Lys39</scene> causes another stabilizing component of the ON7 antagonist. Glu293 forms polar interactions with Lys39, positioning it in close proximity to to the carboxylic acid of ON7, which then interactions with Lys39 via ionic bonding. While Lys39 is highly conserved among all six LPA receptors, a His40 residue is present that is specific to the LPA1 receptor. <scene name='72/721543/His40/1'>His40</scene> forms both ionic and polar interactions with the carboxylic acid of ON7. The protonation of this residue has been found to greatly affect the binding affinity of LPA, and is an important link to tumor growth and survival in acidic environments.<br />
<br />
<br />
== Function ==<br />
The LPA1 receptor has been found to initiate downstream signaling cascades with three [https://en.wikipedia.org/wiki/G_protein G proteins] that signal for cell proliferation, survival, and migration. The LPA1 receptor is present in nearly all cells and tissues throughout the body, and deletion of the LPA1 receptor has been found to have physiological effects on every organ system. Despite this receptor being expressed throughout the body, LPA1 has been found to be expressed highly in neural tissue, aiding in Schwann cell migration and myelination, formation of synapses, and glial cell growth. Recent studies have also found that the LPA1 receptor is important in pain signal initiation via a [https://en.wikipedia.org/wiki/Rho-associated_protein_kinase ROCK] pathway.<br />
<br />
== Disease Relevance ==<br />
The LPA1 receptor, depending on its level of expression, has been linked to both protective functions in the presence of a disease as well as causing a particular illness. For example, in patients with heart diseases, LPA1 has been found to communicate with [[PI3K]], [https://en.wikipedia.org/wiki/Protein_kinase_B PKB], and [[ERK]] to induce a hypertrophic response in the heart in order to offset reduced heart contractions. In addition, due to LPA1's function of pain signaling, overexertion of this protein can cause both [https://en.wikipedia.org/wiki/Allodynia allodynia] or [https://en.wikipedia.org/wiki/Hyperalgesia hyperalgesia], common symptoms of multiple sclerosis or a stroke.<br />
Because of the mitogen signaling activity of LPA1, abnormal expression or mutation of this receptor has been linked to tumor growth, survival, and migration in both liver and lung tumors. As recently discussed, the His40 on LPA1, when protonated, increased LPA binding affinity is increase by up to 1kcal/mol. Because of this, in an acidic environment that is typically produced by [https://en.wikipedia.org/wiki/Tumor_hypoxia hypoxic tumors] creating lactic acid, LPA1 activity is increased, allowing these tumors to continue to proliferate, migrate, and survive. Lastly, due to the function of LPA1 in myelinating Schwann cells, mutation of the receptor can also lead to a decrease in [https://en.wikipedia.org/wiki/Prepulse_inhibition prepulse inhibition], a general sign of schizophrenia.<br />
<br />
== Receptor Comparison ==<br />
<br />
=== Sphingosine 1-Phosphate Receptor ===<br />
LPA1 belongs to the EDG (endothelial differentiation gene) family of [https://en.wikipedia.org/wiki/Lysophospholipid_receptor lysophospholipid receptors]. This family also includes the [https://en.wikipedia.org/wiki/S1PR1 sphingosine 1-phosphate receptor 1] (S1P1), which has many structural similarities to LPA1. In fact, the transmembrane regions share a sequence identity of 41%. A defining difference between these two receptors their mode of ligand access to the binding site. Where as the hydrophobic [https://en.wikipedia.org/wiki/Sphingosine-1-phosphate S1P ligand] enters S1P1 via the membrane, LPA1 has an extracellular opening that allows LPA access from the extracellular space. Structural evidence for this altered ligand pathway include global changes in the positioning of the extracellular loops (ECL) and transmembrane helices (TM). Specifically, this includes slight divergence of <scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene>, which is positioned 3 angstroms closer to TMVII compared to S1P1, and a repositioning of <scene name='72/721543/Ecl_regions/1'>ECL3</scene>, resulting in a divergence of 8 angstroms from S1P1. This narrowing of the gap between TMI and TMVII blocks membrane ligand access, while the greater distance between ECL3 and the other extracellular loops promotes extracellular access. Additionally, ECL0 is helical in S1P1, but lacks secondary structure in LPA1. This increased flexibility that results further promotes favorable access from the extracellular space.<br />
<br />
<scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene><br />
<br />
<scene name='72/721543/Ecl_regions/1'>ECL3</scene><br />
<br />
=== Endocannabinoid Receptor 1 ===<br />
LPA1 also is closely related to the [http://www.nature.com/ijo/journal/v30/n1s/full/0803272a.html cannabinoid receptor] [https://en.wikipedia.org/wiki/Cannabinoid_receptor_type_1 CB1]<br />
<br />
<scene name='72/721543/Asp129_and_trp210/2'>TextToBeDisplayed</scene><br />
<br />
<br />
<br />
<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Chandler Mitchellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1172&diff=2584579Sandbox Reserved 11722016-03-29T12:24:08Z<p>Chandler Mitchell: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Central_Metabolism}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Lysophosphatidic Acid Receptor 1==<br />
<StructureSection load='4z34' size='340' side='right' caption='Cartoon representation of the LPA1 protein and its antagonist, ON7. ([https://en.wikipedia.org/wiki/Protein_Data_Bank PDB] code [http://www.rcsb.org/pdb/explore/explore.do?structureId=4z34 4Z34]) ' scene=''><br />
<br />
<br />
== Introduction ==<br />
[[Image:General_Picture.png |200 px|left|thumb| General image of the LPA1 receptor's seven alpha helices]]<br />
Lysophosphatidic Acid Receptor 1 (commonly referred to as LPA1) is a [[G protein-coupled receptor]] and one of 6 different LPA receptors (LPA1-LPA6) that bind the phospholipid derivative [https://en.wikipedia.org/wiki/Lysophosphatidic_acid lysophosphatidic acid (LPA)], a signaling molecule that acts as a potent mitogen upon binding to one of its six receptors.<ref name="regpeps">PMID: 26091040</ref>, ----------- LPA1 is part of the larger EDG receptor family(link) which includes the more widely known sphingosine 1-phopshate receptors.<br />
== Structure ==<br />
[[Image:ON7.png|200 px|left|thumb|LPA1 receptor in tan, antagonist ON7 in green and red]]<br />
The LPA1 receptor protein is composed of 364 amino acids with a mass of approximately 41 kDa. Just as other G-protein coupled receptors, LPA1 contains seven alpha helices which make up the seven transmembrane spanning domains with three intracellular loops and three extracellular loops. Within these helices is an amphiphilic binding pocket enabling the LPA molecule to bind.<br />
=== Key Ligand Interactions ===<br />
Three separate interactions with an antagonist of LPA1, ON7, help demonstrate the key interactions that stabilize the binding of the LPA phospholipid to this receptor. At the polar region of the binding pocket, the majority of this region is stabilized by <scene name='72/721543/Arg124gln125/1'>Arg124 and Gln125</scene> forming ionic and polar interactions with the carboxylic acid and the hydroxyl group of ON7. In addition, interplay between <scene name='72/721543/Lys39_and_glu293/4'>Glu293 and Lys39</scene> causes another stabilizing component of the ON7 antagonist. Glu293 forms polar interactions with Lys39, positioning it in close proximity to to the carboxylic acid of ON7, which then interactions with Lys39 via ionic bonding. While Lys39 is highly conserved among all six LPA receptors, a His40 residue is present that is specific to the LPA1 receptor. <scene name='72/721543/His40/1'>His40</scene> forms both ionic and polar interactions with the carboxylic acid of ON7. The protonation of this residue has been found to greatly affect the binding affinity of LPA, and is an important link to tumor growth and survival in acidic environments.<br />
<br />
<br />
== Function ==<br />
The LPA1 receptor has been found to initiate downstream signaling cascades with three [https://en.wikipedia.org/wiki/G_protein G proteins] that signal for cell proliferation, survival, and migration. The LPA1 receptor is present in nearly all cells and tissues throughout the body, and deletion of the LPA1 receptor has been found to have physiological effects on every organ system. Despite this receptor being expressed throughout the body, LPA1 has been found to be expressed highly in neural tissue, aiding in Schwann cell migration and myelination, formation of synapses, and glial cell growth. Recent studies have also found that the LPA1 receptor is important in pain signal initiation via a [https://en.wikipedia.org/wiki/Rho-associated_protein_kinase ROCK] pathway.<br />
<br />
== Disease Relevance ==<br />
The LPA1 receptor, depending on its level of expression, has been linked to both protective functions in the presence of a disease as well as causing a particular illness. For example, in patients with heart diseases, LPA1 has been found to communicate with [[PI3K]], [https://en.wikipedia.org/wiki/Protein_kinase_B PKB], and [[ERK]] to induce a hypertrophic response in the heart in order to offset reduced heart contractions. In addition, due to LPA1's function of pain signaling, overexertion of this protein can cause both [https://en.wikipedia.org/wiki/Allodynia allodynia] or [https://en.wikipedia.org/wiki/Hyperalgesia hyperalgesia], common symptoms of multiple sclerosis or a stroke.<br />
Because of the mitogen signaling activity of LPA1, abnormal expression or mutation of this receptor has been linked to tumor growth, survival, and migration in both liver and lung tumors. As recently discussed, the His40 on LPA1, when protonated, increased LPA binding affinity is increase by up to 1kcal/mol. Because of this, in an acidic environment that is typically produced by [https://en.wikipedia.org/wiki/Tumor_hypoxia hypoxic tumors] creating lactic acid, LPA1 activity is increased, allowing these tumors to continue to proliferate, migrate, and survive. Lastly, due to the function of LPA1 in myelinating Schwann cells, mutation of the receptor can also lead to a decrease in [https://en.wikipedia.org/wiki/Prepulse_inhibition prepulse inhibition], a general sign of schizophrenia.<br />
<br />
== Receptor Comparison ==<br />
<br />
=== Sphingosine 1-Phosphate Receptor ===<br />
LPA1 belongs to the EDG (endothelial differentiation gene) family of [https://en.wikipedia.org/wiki/Lysophospholipid_receptor lysophospholipid receptors]. This family also includes the [https://en.wikipedia.org/wiki/S1PR1 sphingosine 1-phosphate receptor 1] (S1P1), which has many structural similarities to LPA1. In fact, the transmembrane regions share a sequence identity of 41%. A defining difference between these two receptors their mode of ligand access to the binding site. Where as the hydrophobic [https://en.wikipedia.org/wiki/Sphingosine-1-phosphate S1P ligand] enters S1P1 via the membrane, LPA1 has an extracellular opening that allows LPA access from the extracellular space. Structural evidence for this altered ligand pathway include global changes in the positioning of the extracellular loops (ECL) and transmembrane helices (TM). Specifically, this includes slight divergence of <scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene>, which is positioned 3 angstroms closer to TMVII compared to S1P1, and a repositioning of <scene name='72/721543/Ecl_regions/1'>ECL3</scene>, resulting in a divergence of 8 angstroms from S1P1. This narrowing of the gap between TMI and TMVII blocks membrane ligand access, while the greater distance between ECL3 and the other extracellular loops promotes extracellular access. Additionally, ECL0 is helical in S1P1, but lacks secondary structure in LPA1. This increased flexibility that results further promotes favorable access from the extracellular space.<br />
<br />
<scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene><br />
<br />
<scene name='72/721543/Ecl_regions/1'>ECL3</scene><br />
<br />
=== Endocannabinoid Receptor 1 === <br />
<br />
<scene name='72/721543/Asp129_and_trp210/2'>TextToBeDisplayed</scene><br />
<br />
<br />
<br />
<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Chandler Mitchellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1172&diff=2584574Sandbox Reserved 11722016-03-29T12:22:06Z<p>Chandler Mitchell: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Central_Metabolism}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Lysophosphatidic Acid Receptor 1==<br />
<StructureSection load='4z34' size='340' side='right' caption='Cartoon representation of the LPA1 protein and its antagonist, ON7. ([https://en.wikipedia.org/wiki/Protein_Data_Bank PDB] code [http://www.rcsb.org/pdb/explore/explore.do?structureId=4z34 4Z34]) ' scene=''><br />
<br />
<br />
== Introduction ==<br />
[[Image:General_Picture.png |200 px|left|thumb| General image of the LPA1 receptor's seven alpha helices]]<br />
Lysophosphatidic Acid Receptor 1 (commonly referred to as LPA1) is a [[G protein-coupled receptor]] and one of 6 different LPA receptors (LPA1-LPA6) that bind the phospholipid derivative [https://en.wikipedia.org/wiki/Lysophosphatidic_acid lysophosphatidic acid (LPA)], a signaling molecule that acts as a potent mitogen upon binding to one of its six receptors.<ref name="regpeps">PMID: 26091040</ref>, ----------- LPA1 is part of the larger EDG receptor family(link) which includes the more widely known sphingosine 1-phopshate receptors.<br />
== Structure ==<br />
[[Image:ON7.png|200 px|left|thumb|LPA1 receptor in tan, antagonist ON7 in green and red]]<br />
The LPA1 receptor protein is composed of 364 amino acids with a mass of approximately 41 kDa. Just as other G-protein coupled receptors, LPA1 contains seven alpha helices which make up the seven transmembrane spanning domains with three intracellular loops and three extracellular loops. Within these helices is an amphiphilic binding pocket enabling the LPA molecule to bind.<br />
=== Key Ligand Interactions ===<br />
Three separate interactions with an antagonist of LPA1, ON7, help demonstrate the key interactions that stabilize the binding of the LPA phospholipid to this receptor. At the polar region of the binding pocket, the majority of this region is stabilized by <scene name='72/721543/Arg124gln125/1'>Arg124 and Gln125</scene> forming ionic and polar interactions with the carboxylic acid and the hydroxyl group of ON7. In addition, interplay between <scene name='72/721543/Lys39_and_glu293/4'>Glu293 and Lys39</scene> causes another stabilizing component of the ON7 antagonist. Glu293 forms polar interactions with Lys39, positioning it in close proximity to to the carboxylic acid of ON7, which then interactions with Lys39 via ionic bonding. While Lys39 is highly conserved among all six LPA receptors, a His40 residue is present that is specific to the LPA1 receptor. <scene name='72/721543/His40/1'>His40</scene> forms both ionic and polar interactions with the carboxylic acid of ON7. The protonation of this residue has been found to greatly affect the binding affinity of LPA, and is an important link to tumor growth and survival in acidic environments.<br />
<br />
<br />
== Function ==<br />
The LPA1 receptor has been found to initiate downstream signaling cascades with three [https://en.wikipedia.org/wiki/G_protein G proteins] that signal for cell proliferation, survival, and migration. The LPA1 receptor is present in nearly all cells and tissues throughout the body, and deletion of the LPA1 receptor has been found to have physiological effects on every organ system. Despite this receptor being expressed throughout the body, LPA1 has been found to be expressed highly in neural tissue, aiding in Schwann cell migration and myelination, formation of synapses, and glial cell growth. Recent studies have also found that the LPA1 receptor is important in pain signal initiation via a [https://en.wikipedia.org/wiki/Rho-associated_protein_kinase ROCK] pathway.<br />
<br />
== Disease Relevance ==<br />
The LPA1 receptor, depending on its level of expression, has been linked to both protective functions in the presence of a disease as well as causing a particular illness. For example, in patients with heart diseases, LPA1 has been found to communicate with [[PI3K]], [https://en.wikipedia.org/wiki/Protein_kinase_B PKB], and [[ERK]] to induce a hypertrophic response in the heart in order to offset reduced heart contractions. In addition, due to LPA1's function of pain signaling, overexertion of this protein can cause both [https://en.wikipedia.org/wiki/Allodynia allodynia] or [https://en.wikipedia.org/wiki/Hyperalgesia hyperalgesia], common symptoms of multiple sclerosis or a stroke.<br />
Because of the mitogen signaling activity of LPA1, abnormal expression or mutation of this receptor has been linked to tumor growth, survival, and migration in both liver and lung tumors. As recently discussed, the His40 on LPA1, when protonated, increased LPA binding affinity is increase by up to 1kcal/mol. Because of this, in an acidic environment that is typically produced by [https://en.wikipedia.org/wiki/Tumor_hypoxia hypoxic tumors] creating lactic acid, LPA1 activity is increased, allowing these tumors to continue to proliferate, migrate, and survive. Lastly, due to the function of LPA1 in myelinating Schwann cells, mutation of the receptor can also lead to a decrease in [https://en.wikipedia.org/wiki/Prepulse_inhibition prepulse inhibition], a general sign of schizophrenia.<br />
<br />
== Receptor Comparison ==<br />
<br />
=== Sphingosine 1-Phosphate Receptor ===<br />
LPA1 belongs to the EDG (endothelial differentiation gene) family of [https://en.wikipedia.org/wiki/Lysophospholipid_receptor lysophospholipid receptors]. This family also includes the [https://en.wikipedia.org/wiki/S1PR1 sphingosine 1-phosphate receptor 1] (S1P1), which has many structural similarities to LPA1. In fact, the transmembrane regions share a sequence identity of 41%. A defining difference between these two receptors their mode of ligand access to the binding site. Where as the hydrophobic [https://en.wikipedia.org/wiki/Sphingosine-1-phosphate S1P ligand] enters S1P1 via the membrane, LPA1 has an extracellular opening that allows LPA access from the extracellular space. Structural evidence for this altered ligand pathway include global changes in the positioning of the extracellular loops (ECL) and transmembrane helices (TM). Specifically, this includes slight divergence of <scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene>, which is positioned 3 angstroms closer to TMVII compared to S1P1, and a repositioning of <scene name='72/721543/Ecl_regions/1'>ECL3</scene>, resulting in a divergence of 8 angstroms form S1P1. This narrowing of the gap between TMI and TMVII blocks membrane ligand access, while the greater distance between ECL3 and the other extracellular loops promotes extracellular access. Additionally, ECL0 is helical in S1P1, but lacks secondary structure in LPA1. This increased flexibility that results further promotes favorable access from the extracellular space.<br />
<br />
<scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene><br />
<br />
<scene name='72/721543/Ecl_regions/1'>ECL3</scene><br />
<br />
=== Endocannabinoid Receptor 1 === <br />
<br />
<scene name='72/721543/Asp129_and_trp210/2'>TextToBeDisplayed</scene><br />
<br />
<br />
<br />
<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Chandler Mitchellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1172&diff=2584570Sandbox Reserved 11722016-03-29T12:20:27Z<p>Chandler Mitchell: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Central_Metabolism}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Lysophosphatidic Acid Receptor 1==<br />
<StructureSection load='4z34' size='340' side='right' caption='Cartoon representation of the LPA1 protein and its antagonist, ON7. ([https://en.wikipedia.org/wiki/Protein_Data_Bank PDB] code [http://www.rcsb.org/pdb/explore/explore.do?structureId=4z34 4Z34]) ' scene=''><br />
<br />
<br />
== Introduction ==<br />
[[Image:General_Picture.png |200 px|left|thumb| General image of the LPA1 receptor's seven alpha helices]]<br />
Lysophosphatidic Acid Receptor 1 (commonly referred to as LPA1) is a [[G protein-coupled receptor]] and one of 6 different LPA receptors (LPA1-LPA6) that bind the phospholipid derivative [https://en.wikipedia.org/wiki/Lysophosphatidic_acid lysophosphatidic acid (LPA)], a signaling molecule that acts as a potent mitogen upon binding to one of the six receptors.<ref name="regpeps">PMID: 26091040</ref>, ----------- LPA1 is part of the larger EDG receptor family(link) which includes the more widely known sphingosine 1-phopshate receptors.<br />
== Structure ==<br />
[[Image:ON7.png|200 px|left|thumb|LPA1 receptor in tan, antagonist ON7 in green and red]]<br />
The LPA1 receptor protein is composed of 364 amino acids with a mass of approximately 41 kDa. Just as other G-protein coupled receptors, LPA1 contains seven alpha helices which make up the seven transmembrane spanning domains with three intracellular loops and three extracellular loops. Within these helices is an amphiphilic binding pocket enabling the LPA molecule to bind.<br />
=== Key Ligand Interactions ===<br />
Three separate interactions with an antagonist of LPA1, ON7, help demonstrate the key interactions that stabilize the binding of the LPA phospholipid to this receptor. At the polar region of the binding pocket, the majority of this region is stabilized by <scene name='72/721543/Arg124gln125/1'>Arg124 and Gln125</scene> forming ionic and polar interactions with the carboxylic acid and the hydroxyl group of ON7. In addition, interplay between <scene name='72/721543/Lys39_and_glu293/4'>Glu293 and Lys39</scene> causes another stabilizing component of the ON7 antagonist. Glu293 forms polar interactions with Lys39, positioning it in close proximity to to the carboxylic acid of ON7, which then interactions with Lys39 via ionic bonding. While Lys39 is highly conserved among all six LPA receptors, a His40 residue is present that is specific to the LPA1 receptor. <scene name='72/721543/His40/1'>His40</scene> forms both ionic and polar interactions with the carboxylic acid of ON7. The protonation of this residue has been found to greatly affect the binding affinity of LPA, and is an important link to tumor growth and survival in acidic environments.<br />
<br />
<br />
== Function ==<br />
The LPA1 receptor has been found to initiate downstream signaling cascades with three [https://en.wikipedia.org/wiki/G_protein G proteins] that signal for cell proliferation, survival, and migration. The LPA1 receptor is present in nearly all cells and tissues throughout the body, and deletion of the LPA1 receptor has been found to have physiological effects on every organ system. Despite this receptor being expressed throughout the body, LPA1 has been found to be expressed highly in neural tissue, aiding in Schwann cell migration and myelination, formation of synapses, and glial cell growth. Recent studies have also found that the LPA1 receptor is important in pain signal initiation via a [https://en.wikipedia.org/wiki/Rho-associated_protein_kinase ROCK] pathway.<br />
<br />
== Disease Relevance ==<br />
The LPA1 receptor, depending on its level of expression, has been linked to both protective functions in the presence of a disease as well as causing a particular illness. For example, in patients with heart diseases, LPA1 has been found to communicate with [[PI3K]], [https://en.wikipedia.org/wiki/Protein_kinase_B PKB], and [[ERK]] to induce a hypertrophic response in the heart in order to offset reduced heart contractions. In addition, due to LPA1's function of pain signaling, overexertion of this protein can cause both [https://en.wikipedia.org/wiki/Allodynia allodynia] or [https://en.wikipedia.org/wiki/Hyperalgesia hyperalgesia], common symptoms of multiple sclerosis or a stroke.<br />
Because of the mitogen signaling activity of LPA1, abnormal expression or mutation of this receptor has been linked to tumor growth, survival, and migration in both liver and lung tumors. As recently discussed, the His40 on LPA1, when protonated, increased LPA binding affinity is increase by up to 1kcal/mol. Because of this, in an acidic environment that is typically produced by [https://en.wikipedia.org/wiki/Tumor_hypoxia hypoxic tumors] creating lactic acid, LPA1 activity is increased, allowing these tumors to continue to proliferate, migrate, and survive. Lastly, due to the function of LPA1 in myelinating Schwann cells, mutation of the receptor can also lead to a decrease in [https://en.wikipedia.org/wiki/Prepulse_inhibition prepulse inhibition], a general sign of schizophrenia.<br />
<br />
== Receptor Comparison ==<br />
<br />
=== Sphingosine 1-Phosphate Receptor ===<br />
LPA1 belongs to the EDG (endothelial differentiation gene) family of [https://en.wikipedia.org/wiki/Lysophospholipid_receptor lysophospholipid receptors]. This family also includes the [https://en.wikipedia.org/wiki/S1PR1 sphingosine 1-phosphate receptor 1] (S1P1), which has many structural similarities to LPA1. In fact, the transmembrane regions share a sequence identity of 41%. A defining difference between these two receptors their mode of ligand access to the binding site. Where as the hydrophobic [https://en.wikipedia.org/wiki/Sphingosine-1-phosphate S1P ligand] enters S1P1 via the membrane, LPA1 has an extracellular opening that allows LPA access from the extracellular space. Structural evidence for this altered ligand pathway include global changes in the positioning of the extracellular loops (ECL) and transmembrane helices (TM). Specifically, this includes slight divergence of <scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene>, which is positioned 3 angstroms closer to TMVII compared to S1P1, and a repositioning of <scene name='72/721543/Ecl_regions/1'>ECL3</scene>, resulting in a divergence of 8 angstroms form S1P1. This narrowing of the gap between TMI and TMVII blocks membrane ligand access, while the greater distance between ECL3 and the other extracellular loops promotes extracellular access. Additionally, ECL0 is helical in S1P1, but lacks secondary structure in LPA1. This increased flexibility that results further promotes favorable access from the extracellular space.<br />
<br />
<scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene><br />
<br />
<scene name='72/721543/Ecl_regions/1'>ECL3</scene><br />
<br />
=== Endocannabinoid Receptor 1 === <br />
<br />
<scene name='72/721543/Asp129_and_trp210/2'>TextToBeDisplayed</scene><br />
<br />
<br />
<br />
<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Chandler Mitchellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1172&diff=2584561Sandbox Reserved 11722016-03-29T12:16:12Z<p>Chandler Mitchell: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Central_Metabolism}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Lysophosphatidic Acid Receptor 1==<br />
<StructureSection load='4z34' size='340' side='right' caption='Cartoon representation of the LPA1 protein and its antagonist, ON7. ([https://en.wikipedia.org/wiki/Protein_Data_Bank PDB] code [http://www.rcsb.org/pdb/explore/explore.do?structureId=4z34 4Z34]) ' scene=''><br />
<br />
<br />
== Introduction ==<br />
[[Image:General_Picture.png |200 px|left|thumb| General image of the LPA1 receptor's seven alpha helices]]<br />
Lysophosphatidic Acid Receptor 1 (commonly referred to as LPA1) is a [[G protein-coupled receptor]] and one of 6 different LPA receptors (LPA1-LPA6) that bind the phospholipid derivative [https://en.wikipedia.org/wiki/Lysophosphatidic_acid lysophosphatidic acid (LPA)], a signaling molecule that acts as a potent mitogen upon binding to one of the six receptors. ----------- LPA1 is part of the larger EDG receptor family(link) which includes the more widely known sphingosine 1-phopshate receptors.<br />
== Structure ==<br />
[[Image:ON7.png|200 px|left|thumb|LPA1 receptor in tan, antagonist ON7 in green and red]]<br />
The LPA1 receptor protein is composed of 364 amino acids with a mass of approximately 41 kDa. Just as other G-protein coupled receptors, LPA1 contains seven alpha helices which make up the seven transmembrane spanning domains with three intracellular loops and three extracellular loops. Within these helices is an amphiphilic binding pocket enabling the LPA molecule to bind.<br />
=== Key Ligand Interactions ===<br />
Three separate interactions with an antagonist of LPA1, ON7, help demonstrate the key interactions that stabilize the binding of the LPA phospholipid to this receptor. At the polar region of the binding pocket, the majority of this region is stabilized by <scene name='72/721543/Arg124gln125/1'>Arg124 and Gln125</scene> forming ionic and polar interactions with the carboxylic acid and the hydroxyl group of ON7. In addition, interplay between <scene name='72/721543/Lys39_and_glu293/4'>Glu293 and Lys39</scene> causes another stabilizing component of the ON7 antagonist. Glu293 forms polar interactions with Lys39, positioning it in close proximity to to the carboxylic acid of ON7, which then interactions with Lys39 via ionic bonding. While Lys39 is highly conserved among all six LPA receptors, a His40 residue is present that is specific to the LPA1 receptor. <scene name='72/721543/His40/1'>His40</scene> forms both ionic and polar interactions with the carboxylic acid of ON7. The protonation of this residue has been found to greatly affect the binding affinity of LPA, and is an important link to tumor growth and survival in acidic environments.<br />
<br />
<br />
== Function ==<br />
The LPA1 receptor has been found to initiate downstream signaling cascades with three [https://en.wikipedia.org/wiki/G_protein G proteins] that signal for cell proliferation, survival, and migration. The LPA1 receptor is present in nearly all cells and tissues throughout the body, and deletion of the LPA1 receptor has been found to have physiological effects on every organ system. Despite this receptor being expressed throughout the body, LPA1 has been found to be expressed highly in neural tissue, aiding in Schwann cell migration and myelination, formation of synapses, and glial cell growth. Recent studies have also found that the LPA1 receptor is important in pain signal initiation via a [https://en.wikipedia.org/wiki/Rho-associated_protein_kinase ROCK] pathway.<br />
<br />
== Disease Relevance ==<br />
The LPA1 receptor, depending on its level of expression, has been linked to both protective functions in the presence of a disease as well as causing a particular illness. For example, in patients with heart diseases, LPA1 has been found to communicate with [[PI3K]], [https://en.wikipedia.org/wiki/Protein_kinase_B PKB], and [[ERK]] to induce a hypertrophic response in the heart in order to offset reduced heart contractions. In addition, due to LPA1's function of pain signaling, overexertion of this protein can cause both [https://en.wikipedia.org/wiki/Allodynia allodynia] or [https://en.wikipedia.org/wiki/Hyperalgesia hyperalgesia], common symptoms of multiple sclerosis or a stroke.<br />
Because of the mitogen signaling activity of LPA1, abnormal expression or mutation of this receptor has been linked to tumor growth, survival, and migration in both liver and lung tumors. As recently discussed, the His40 on LPA1, when protonated, increased LPA binding affinity is increase by up to 1kcal/mol. Because of this, in an acidic environment that is typically produced by [https://en.wikipedia.org/wiki/Tumor_hypoxia hypoxic tumors] creating lactic acid, LPA1 activity is increased, allowing these tumors to continue to proliferate, migrate, and survive. Lastly, due to the function of LPA1 in myelinating Schwann cells, mutation of the receptor can also lead to a decrease in [https://en.wikipedia.org/wiki/Prepulse_inhibition prepulse inhibition], a general sign of schizophrenia.<br />
<br />
== Receptor Comparison ==<br />
<br />
=== Sphingosine 1-Phosphate Receptor ===<br />
LPA1 belongs to the EDG (endothelial differentiation gene) family of [https://en.wikipedia.org/wiki/Lysophospholipid_receptor lysophospholipid receptors]. This family also includes the [https://en.wikipedia.org/wiki/S1PR1 sphingosine 1-phosphate receptor 1] (S1P1), which has many structural similarities to LPA1. In fact, the transmembrane regions share a sequence identity of 41%. A defining difference between these two receptors their mode of ligand access to the binding site. Where as the hydrophobic S1P ligand enters S1P1 via the membrane, LPA1 has an extracellular opening that allows LPA access from the extracellular space. Structural evidence for this altered ligand pathway include global changes in the positioning of the extracellular loops (ECL) and transmembrane helices (TM). Specifically, this includes slight divergence of <scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene>, which is positioned 3 angstroms closer to TMVII compared to S1P1, and a repositioning of <scene name='72/721543/Ecl_regions/1'>ECL3</scene>, resulting in a divergence of 8 angstroms form S1P1. This narrowing of the gap between TMI and TMVII blocks membrane ligand access, while the greater distance between ECL3 and the other extracellular loops promotes extracellular access. Additionally, ECL0 is helical in S1P1, but lacks secondary structure in LPA1. This increased flexibility that results further promotes favorable access from the extracellular space.<br />
<br />
<scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene><br />
<br />
<scene name='72/721543/Ecl_regions/1'>ECL3</scene><br />
<br />
=== Endocannabinoid Receptor 1 === <br />
<br />
<scene name='72/721543/Asp129_and_trp210/2'>TextToBeDisplayed</scene><br />
<br />
<br />
<br />
<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Chandler Mitchellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1172&diff=2584548Sandbox Reserved 11722016-03-29T12:10:53Z<p>Chandler Mitchell: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Central_Metabolism}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Lysophosphatidic Acid Receptor 1==<br />
<StructureSection load='4z34' size='340' side='right' caption='Cartoon representation of the LPA1 protein and its antagonist, ON7. ([https://en.wikipedia.org/wiki/Protein_Data_Bank PDB] code [http://www.rcsb.org/pdb/explore/explore.do?structureId=4z34 4Z34]) ' scene=''><br />
<br />
<br />
== Introduction ==<br />
[[Image:General_Picture.png |200 px|left|thumb| General image of the LPA1 receptor's seven alpha helices]]<br />
Lysophosphatidic Acid Receptor 1 (commonly referred to as LPA1) is a [[G protein-coupled receptor]] and one of 6 different LPA receptors (LPA1-LPA6) that bind the phospholipid derivative [https://en.wikipedia.org/wiki/Lysophosphatidic_acid lysophosphatidic acid (LPA)], a signaling molecule that acts as a potent mitogen upon binding to one of the six receptors. ----------- LPA1 is part of the larger EDG receptor family(link) which includes the more widely known sphingosine 1-phopshate receptors.<br />
== Structure ==<br />
[[Image:ON7.png|200 px|left|thumb|LPA1 receptor in tan, antagonist ON7 in green and red]]<br />
The LPA1 receptor protein is composed of 364 amino acids with a mass of approximately 41 kDa. Just as other G-protein coupled receptors, LPA1 contains seven alpha helices which make up the seven transmembrane spanning domains with three intracellular loops and three extracellular loops. Within these helices is an amphiphilic binding pocket enabling the LPA molecule to bind.<br />
=== Key Ligand Interactions ===<br />
Three separate interactions with an antagonist of LPA1, ON7, help demonstrate the key interactions that stabilize the binding of the LPA phospholipid to this receptor. At the polar region of the binding pocket, the majority of this region is stabilized by <scene name='72/721543/Arg124gln125/1'>Arg124 and Gln125</scene> forming ionic and polar interactions with the carboxylic acid and the hydroxyl group of ON7. In addition, interplay between <scene name='72/721543/Lys39_and_glu293/4'>Glu293 and Lys39</scene> causes another stabilizing component of the ON7 antagonist. Glu293 forms polar interactions with Lys39, positioning it in close proximity to to the carboxylic acid of ON7, which then interactions with Lys39 via ionic bonding. While Lys39 is highly conserved among all six LPA receptors, a His40 residue is present that is specific to the LPA1 receptor. <scene name='72/721543/His40/1'>His40</scene> forms both ionic and polar interactions with the carboxylic acid of ON7. The protonation of this residue has been found to greatly affect the binding affinity of LPA, and is an important link to tumor growth and survival in acidic environments.<br />
<br />
<br />
== Function ==<br />
The LPA1 receptor has been found to initiate downstream signaling cascades with three [https://en.wikipedia.org/wiki/G_protein G proteins] that signal for cell proliferation, survival, and migration. The LPA1 receptor is present in nearly all cells and tissues throughout the body, and deletion of the LPA1 receptor has been found to have physiological effects on every organ system. Despite this receptor being expressed throughout the body, LPA1 has been found to be expressed highly in neural tissue, aiding in Schwann cell migration and myelination, formation of synapses, and glial cell growth. Recent studies have also found that the LPA1 receptor is important in pain signal initiation via a [https://en.wikipedia.org/wiki/Rho-associated_protein_kinase ROCK] pathway.<br />
<br />
== Disease Relevance ==<br />
The LPA1 receptor, depending on its level of expression, has been linked to both protective functions in the presence of a disease as well as causing a particular illness. For example, in patients with heart diseases, LPA1 has been found to communicate with [[PI3K]], [https://en.wikipedia.org/wiki/Protein_kinase_B PKB], and [[ERK]] to induce a hypertrophic response in the heart in order to offset reduced heart contractions. In addition, due to LPA1's function of pain signaling, overexertion of this protein can cause both [https://en.wikipedia.org/wiki/Allodynia allodynia] or [https://en.wikipedia.org/wiki/Hyperalgesia hyperalgesia], common symptoms of multiple sclerosis or a stroke.<br />
Because of the mitogen signaling activity of LPA1, abnormal expression or mutation of this receptor has been linked to tumor growth, survival, and migration in both liver and lung tumors. As recently discussed, the His40 on LPA1, when protonated, increased LPA binding affinity is increase by up to 1kcal/mol. Because of this, in an acidic environment that is typically produced by [https://en.wikipedia.org/wiki/Tumor_hypoxia hypoxic tumors] creating lactic acid, LPA1 activity is increased, allowing these tumors to continue to proliferate, migrate, and survive. Lastly, due to the function of LPA1 in myelinating Schwann cells, mutation of the receptor can also lead to a decrease in [https://en.wikipedia.org/wiki/Prepulse_inhibition prepulse inhibition], a general sign of schizophrenia.<br />
<br />
== Receptor Comparison ==<br />
<br />
=== Sphingosine 1-Phosphate Receptor ===<br />
LPA1 belongs to the EDG (endothelial differentiation gene) family of [https://en.wikipedia.org/wiki/Lysophospholipid_receptor lysophospholipid receptors]. This family also includes the sphingosine 1-phosphate receptor 1 (S1P1), which has many structural similarities to LPA1. In fact, the transmembrane regions share a sequence identity of 41%. A defining difference between these two receptors their mode of ligand access to the binding site. Where as the hydrophobic S1P ligand enters S1P1 via the membrane, LPA1 has an extracellular opening that allows LPA access from the extracellular space. Structural evidence for this altered ligand pathway include global changes in the positioning of the extracellular loops (ECL) and transmembrane helices (TM). Specifically, this includes slight divergence of <scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene>, which is positioned 3 angstroms closer to TMVII compared to S1P1, and a repositioning of <scene name='72/721543/Ecl_regions/1'>ECL3</scene>, resulting in a divergence of 8 angstroms form S1P1. This narrowing of the gap between TMI and TMVII blocks membrane ligand access, while the greater distance between ECL3 and the other extracellular loops promotes extracellular access. Additionally, ECL0 is helical in S1P1, but lacks secondary structure in LPA1. This increased flexibility that results further promotes favorable access from the extracellular space.<br />
<br />
<scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene><br />
<br />
<scene name='72/721543/Ecl_regions/1'>ECL3</scene><br />
<br />
=== Endocannabinoid Receptor 1 === <br />
<br />
<scene name='72/721543/Asp129_and_trp210/2'>TextToBeDisplayed</scene><br />
<br />
<br />
<br />
<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Chandler Mitchellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1172&diff=2584541Sandbox Reserved 11722016-03-29T12:07:39Z<p>Chandler Mitchell: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Central_Metabolism}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Lysophosphatidic Acid Receptor 1==<br />
<StructureSection load='4z34' size='340' side='right' caption='Cartoon representation of the LPA1 protein and its antagonist, ON7. ([https://en.wikipedia.org/wiki/Protein_Data_Bank PDB] code [http://www.rcsb.org/pdb/explore/explore.do?structureId=4z34 4Z34]) ' scene=''><br />
<br />
<br />
== Introduction ==<br />
[[Image:General_Picture.png |200 px|left|thumb| General image of the LPA1 receptor's seven alpha helices]]<br />
Lysophosphatidic Acid Receptor 1 (commonly referred to as LPA1) is a [[G protein-coupled receptor]] and one of 6 different LPA receptors (LPA1-LPA6) that bind the phospholipid derivative [https://en.wikipedia.org/wiki/Lysophosphatidic_acid lysophosphatidic acid (LPA)], a signaling molecule that acts as a potent mitogen upon binding to one of the six receptors. ----------- LPA1 is part of the larger EDG receptor family(link) which includes the more widely known sphingosine 1-phopshate receptors.<br />
== Structure ==<br />
[[Image:ON7.png|200 px|left|thumb|LPA1 receptor in tan, antagonist ON7 in green and red]]<br />
The LPA1 receptor protein is composed of 364 amino acids with a mass of approximately 41 kDa. Just as other G-protein coupled receptors, LPA1 contains seven alpha helices which make up the seven transmembrane spanning domains with three intracellular loops and three extracellular loops. Within these helices is an amphiphilic binding pocket enabling the LPA molecule to bind.<br />
=== Key Ligand Interactions ===<br />
Three separate interactions with an antagonist of LPA1, ON7, help demonstrate the key interactions that stabilize the binding of the LPA phospholipid to this receptor. At the polar region of the binding pocket, the majority of this region is stabilized by <scene name='72/721543/Arg124gln125/1'>Arg124 and Gln125</scene> forming ionic and polar interactions with the carboxylic acid and the hydroxyl group of ON7. In addition, interplay between <scene name='72/721543/Lys39_and_glu293/4'>Glu293 and Lys39</scene> causes another stabilizing component of the ON7 antagonist. Glu293 forms polar interactions with Lys39, positioning it in close proximity to to the carboxylic acid of ON7, which then interactions with Lys39 via ionic bonding. While Lys39 is highly conserved among all six LPA receptors, a His40 residue is present that is specific to the LPA1 receptor. <scene name='72/721543/His40/1'>His40</scene> forms both ionic and polar interactions with the carboxylic acid of ON7. The protonation of this residue has been found to greatly affect the binding affinity of LPA, and is an important link to tumor growth and survival in acidic environments.<br />
<br />
<br />
== Function ==<br />
The LPA1 receptor has been found to initiate downstream signaling cascades with three [https://en.wikipedia.org/wiki/G_protein G proteins] that signal for cell proliferation, survival, and migration. The LPA1 receptor is present in nearly all cells and tissues throughout the body, and deletion of the LPA1 receptor has been found to have physiological effects on every organ system. Despite this receptor being expressed throughout the body, LPA1 has been found to be expressed highly in neural tissue, aiding in Schwann cell migration and myelination, formation of synapses, and glial cell growth. Recent studies have also found that the LPA1 receptor is important in pain signal initiation via a [https://en.wikipedia.org/wiki/Rho-associated_protein_kinase ROCK] pathway.<br />
<br />
== Disease Relevance ==<br />
The LPA1 receptor, depending on its level of expression, has been linked to both protective functions in the presence of a disease as well as causing a particular illness. For example, in patients with heart diseases, LPA1 has been found to communicate with [[PI3K]], [https://en.wikipedia.org/wiki/Protein_kinase_B PKB], and [[ERK]] to induce a hypertrophic response in the heart in order to offset reduced heart contractions. In addition, due to LPA1's function of pain signaling, overexertion of this protein can cause both [https://en.wikipedia.org/wiki/Allodynia allodynia] or [https://en.wikipedia.org/wiki/Hyperalgesia hyperalgesia], common symptoms of multiple sclerosis or a stroke.<br />
Because of the mitogen signaling activity of LPA1, abnormal expression or mutation of this receptor has been linked to tumor growth, survival, and migration in both liver and lung tumors. As recently discussed, the His40 on LPA1, when protonated, increased LPA binding affinity is increase by up to 1kcal/mol. Because of this, in an acidic environment that is typically produced by [https://en.wikipedia.org/wiki/Tumor_hypoxia hypoxic tumors] creating lactic acid, LPA1 activity is increased, allowing these tumors to continue to proliferate, migrate, and survive. Lastly, due to the function of LPA1 in myelinating Schwann cells, mutation of the receptor can also lead to a decrease in [https://en.wikipedia.org/wiki/Prepulse_inhibition prepulse inhibition], a general sign of schizophrenia.<br />
<br />
== Receptor Comparison ==<br />
<br />
=== Sphingosine 1-Phosphate Receptor ===<br />
LPA1 belongs to the EDG (endothelial differentiation gene) family of lysophospholipid receptors. This family also includes the sphingosine 1-phosphate receptor 1 (S1P1), which has many structural similarities to LPA1. In fact, the transmembrane regions share a sequence identity of 41%. A defining difference between these two receptors their mode of ligand access to the binding site. Where as the hydrophobic S1P ligand enters S1P1 via the membrane, LPA1 has an extracellular opening that allows LPA access from the extracellular space. Structural evidence for this altered ligand pathway include global changes in the positioning of the extracellular loops (ECL) and transmembrane helices (TM). Specifically, this includes slight divergence of <scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene>, which is positioned 3 angstroms closer to TMVII compared to S1P1, and a repositioning of <scene name='72/721543/Ecl_regions/1'>ECL3</scene>, resulting in a divergence of 8 angstroms form S1P1. This narrowing of the gap between TMI and TMVII blocks membrane ligand access, while the greater distance between ECL3 and the other extracellular loops promotes extracellular access. Additionally, ECL0 is helical in S1P1, but lacks secondary structure in LPA1. This increased flexibility that results further promotes favorable access from the extracellular space.<br />
<br />
<scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene><br />
<br />
<scene name='72/721543/Ecl_regions/1'>ECL3</scene><br />
<br />
=== Endocannabinoid Receptor 1 === <br />
<br />
<scene name='72/721543/Asp129_and_trp210/2'>TextToBeDisplayed</scene><br />
<br />
<br />
<br />
<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Chandler Mitchellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1172&diff=2584465Sandbox Reserved 11722016-03-29T04:37:27Z<p>Chandler Mitchell: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Central_Metabolism}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Lysophosphatidic Acid Receptor 1==<br />
<StructureSection load='4z34' size='340' side='right' caption='Cartoon representation of the LPA1 protein and its antagonist, ON7. ([https://en.wikipedia.org/wiki/Protein_Data_Bank PDB] code [http://www.rcsb.org/pdb/explore/explore.do?structureId=4z34 4Z34]) ' scene=''><br />
<br />
<br />
== Introduction ==<br />
[[Image:General_Picture.png |200 px|left|thumb| General image of the LPA1 receptor's seven alpha helices]]<br />
Lysophosphatidic Acid Receptor 1 (commonly referred to as LPA1) is a [[G protein-coupled receptor]] and one of 6 different LPA receptors (LPA1-LPA6) that bind the phospholipid derivative [https://en.wikipedia.org/wiki/Lysophosphatidic_acid lysophosphatidic acid (LPA)], a signaling molecule that acts as a potent mitogen upon binding to one of the six receptors. ----------- LPA1 is part of the larger EDG receptor family(link) which includes the more widely known sphingosine 1-phopshate receptors.<br />
== Structure ==<br />
[[Image:ON7.png|200 px|left|thumb|LPA1 receptor in tan, antagonist ON7 in green and red]]<br />
The LPA1 receptor protein is composed of 364 amino acids with a mass of approximately 41 kDa. Just as other G-protein coupled receptors, LPA1 contains seven alpha helices which make up the seven transmembrane spanning domains with three intracellular loops and three extracellular loops. Within these helices is an amphiphilic binding pocket enabling the LPA molecule to bind.<br />
=== Key Ligand Interactions ===<br />
Three separate interactions an antagonist of LPA1, ON7, help demonstrate the key interactions that stabilize the binding of the LPA phospholipid to this receptor. At the polar region of the binding pocket, the majority of this region is stabilized by <scene name='72/721543/Arg124gln125/1'>Arg124 and Gln125</scene> forming ionic and polar interactions with the carboxylic acid and the hydroxyl group of ON7. In addition, interplay between <scene name='72/721543/Lys39_and_glu293/4'>Glu293 and Lys39</scene> causes another stabilizing component of the ON7 antagonist. Glu293 forms polar interactions with Lys39, positioning it in close proximity to to the carboxylic acid of ON7, which then interactions with Lys39 via ionic bonding. While Lys39 is highly conserved among all six LPA receptors, a His40 residue is present that is specific to the LPA1 receptor. <scene name='72/721543/His40/1'>His40</scene> forms both ionic and polar interactions with the carboxylic acid of ON7. The protonation of this residue has been found to greatly affect the binding affinity of LPA, and is an important link to tumor growth and survival in acidic environments.<br />
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== Function ==<br />
The LPA1 receptor has been found to initiate downstream signaling cascades with three [https://en.wikipedia.org/wiki/G_protein G proteins] that signal for cell proliferation, survival, and migration. The LPA1 receptor is present in nearly all cells and tissues throughout the body, and deletion of the LPA1 receptor has been found to have physiological effects on every organ system. Despite this receptor being expressed throughout the body, LPA1 has been found to be expressed highly in neural tissue, aiding in Schwann cell migration and myelination, formation of synapses, and glial cell growth. Recent studies have also found that the LPA1 receptor is important in pain signal initiation via a [https://en.wikipedia.org/wiki/Rho-associated_protein_kinase ROCK] pathway.<br />
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== Disease Relevance ==<br />
The LPA1 receptor, depending on its level of expression, has been linked to both protective functions in the presence of a disease as well as causing a particular illness. For example, in patients with heart diseases, LPA1 has been found to communicate with [[PI3K]], [https://en.wikipedia.org/wiki/Protein_kinase_B PKB], and [[ERK]] to induce a hypertrophic response in the heart in order to offset reduced heart contractions. In addition, due to LPA1's function of pain signaling, overexertion of this protein can cause both [https://en.wikipedia.org/wiki/Allodynia allodynia] or [https://en.wikipedia.org/wiki/Hyperalgesia hyperalgesia], common symptoms of multiple sclerosis or a stroke.<br />
Because of the mitogen signaling activity of LPA1, abnormal expression or mutation of this receptor has been linked to tumor growth, survival, and migration in both liver and lung tumors. As recently discussed, the His40 on LPA1, when protonated, increased LPA binding affinity is increase by up to 1kcal/mol. Because of this, in an acidic environment that is typically produced by [https://en.wikipedia.org/wiki/Tumor_hypoxia hypoxic tumors] creating lactic acid, LPA1 activity is increased, allowing these tumors to continue to proliferate, migrate, and survive. Lastly, due to the function of LPA1 in myelinating Schwann cells, mutation of the receptor can also lead to a decrease in [https://en.wikipedia.org/wiki/Prepulse_inhibition prepulse inhibition], a general sign of schizophrenia.<br />
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== Receptor Comparison ==<br />
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=== Sphingosine 1-Phosphate Receptor ===<br />
LPA1 belongs to the EDG family of lysophospholipid receptors. This family also includes the sphingosine 1-phosphate receptor 1 (S1P1), which has many structural similarities to LPA1. In fact, the transmembrane regions share a sequence identity of 41%. A defining difference between these two receptors their mode of ligand access to the binding site. Where as the hydrophobic S1P ligand enters S1P1 via the membrane, LPA1 has an extracellular opening that allows LPA access from the extracellular space. Structural evidence for this altered ligand pathway include global changes in the positioning of the extracellular loops (ECL) and transmembrane helices (TM). Specifically, this includes slight divergence of <scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene>, which is positioned 3 angstroms closer to TMVII compared to S1P1, and a repositioning of <scene name='72/721543/Ecl_regions/1'>ECL3</scene>, resulting in a divergence of 8 angstroms form S1P1. This narrowing of the gap between TMI and TMVII blocks membrane ligand access, while the greater distance between ECL3 and the other extracellular loops promotes extracellular access. Additionally, ECL0 is helical in S1P1, but lacks secondary structure in LPA1. This increased flexibility that results further promotes favorable access from the extracellular space.<br />
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<scene name='72/721543/Tmvii_and_tmi/1'>TMI</scene><br />
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=== Endocannabinoid Receptor 1 === <br />
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== References ==<br />
<references/></div>Chandler Mitchellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1172&diff=2583395Sandbox Reserved 11722016-03-22T13:26:40Z<p>Chandler Mitchell: </p>
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<div>{{Sandbox_Reserved_CH462_Central_Metabolism}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Lysophosphatidic Acid Receptor 1==<br />
<StructureSection load='4z34' size='340' side='right' caption='Caption for this structure' scene=''><br />
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== Introduction ==<br />
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== Structure ==<br />
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=== Key Ligand Interactions ===<br />
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<scene name='72/721543/Lys39_and_glu293/4'>GluLys</scene><br />
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== Function ==<br />
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== Disease Relevance ==<br />
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== Receptor Comparison ==<br />
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=== Sphingosine 1-Phosphate Receptor ===<br />
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<scene name='72/721543/Tmvii_and_tmi/1'>TextToBeDisplayed</scene><br />
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=== Endocannabinoid Receptor 1 === <br />
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This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
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</StructureSection><br />
== References ==<br />
<references/></div>Chandler Mitchellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1172&diff=2583323Sandbox Reserved 11722016-03-22T12:48:43Z<p>Chandler Mitchell: </p>
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<div>{{Sandbox_Reserved_CH462_Central_Metabolism}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Lysophosphatidic Acid Receptor 1==<br />
<StructureSection load='4z34' size='340' side='right' caption='Caption for this structure' scene=''><br />
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== Introduction ==<br />
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== Structure ==<br />
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=== Key Ligand Interactions ===<br />
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== Function ==<br />
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== Disease Relevance ==<br />
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== Receptor Comparison ==<br />
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=== Sphingosine 1-Phosphate Receptor ===<br />
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<scene name='72/721543/Tmvii_and_tmi/1'>TextToBeDisplayed</scene><br />
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=== Endocannabinoid Receptor 1 === <br />
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This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
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</StructureSection><br />
== References ==<br />
<references/></div>Chandler Mitchellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1172&diff=2582676Sandbox Reserved 11722016-03-15T12:27:21Z<p>Chandler Mitchell: </p>
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<div>{{Sandbox_Reserved_CH462_Central_Metabolism}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Lysophosphatidic Acid Receptor 1==<br />
<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''><br />
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<br />
== Introduction ==<br />
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== Structure ==<br />
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=== Key Ligand Interactions ===<br />
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== Function ==<br />
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== Disease Relevance ==<br />
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== Receptor Comparison ==<br />
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=== Sphingosine 1-Phosphate Receptor ===<br />
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=== Endocannabinoid Receptor 1 === <br />
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This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
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</StructureSection><br />
== References ==<br />
<references/></div>Chandler Mitchellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1172&diff=2582675Sandbox Reserved 11722016-03-15T12:26:14Z<p>Chandler Mitchell: </p>
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<div>{{Sandbox_Reserved_CH462_Central_Metabolism}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Lysophosphatidic Acid Receptor 1==<br />
<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''><br />
This is a default text for your page ''''''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
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== Introduction ==<br />
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== Structure ==<br />
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=== Key Ligand Interactions ===<br />
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== Function ==<br />
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== Disease Relevance ==<br />
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== Receptor Comparison ==<br />
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=== Sphingosine 1-Phosphate Receptor ===<br />
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=== Endocannabinoid Receptor 1 === <br />
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== References ==<br />
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This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
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</StructureSection><br />
== References ==<br />
<references/></div>Chandler Mitchellhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1172&diff=2582673Sandbox Reserved 11722016-03-15T12:25:39Z<p>Chandler Mitchell: </p>
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<div>{{Sandbox_Reserved_CH462_Central_Metabolism}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Lysophosphatidic Acid Receptor 1==<br />
<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''><br />
This is a default text for your page ''''''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
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== Introduction ==<br />
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== Structure ==<br />
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=== Key Ligand Interactions ===<br />
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== Function ==<br />
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== Disease Relevance ==<br />
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== Receptor Comparison ==<br />
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=== Sphingosine 1-Phosphate Receptor ===<br />
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=== Endocannabinoid Receptor 1 === <br />
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This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
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</StructureSection><br />
== References ==<br />
<references/></div>Chandler Mitchellhttps://proteopedia.org/index.php?title=User:Chandler_Mitchell/Sandbox_1&diff=2577904User:Chandler Mitchell/Sandbox 12016-03-01T14:48:32Z<p>Chandler Mitchell: </p>
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<div>==LPA1 Receptor (''Homo sapiens'')==<br />
[[Image:General Pic.png|100 px|left|thumb|Figure Legend]]<br />
<StructureSection load='4z34' size='340' side='right' caption='Caption for this structure' scene=''><br />
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<scene name='72/726407/Residues_25-50/1'>Residues 25-50</scene><br />
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== Function ==<br />
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This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
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</StructureSection><br />
== References ==<br />
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<div>==LPA1 Receptor (''Homo sapiens'')==<br />
[[Image:General Pic.png|100 px|left|thumb|Figure Legend]]<br />
<StructureSection load='4z34' size='340' side='right' caption='Caption for this structure' scene=''><br />
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== Function ==<br />
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== Pharmacology ==<br />
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=== CB1 ===<br />
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== Relevance ==<br />
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== Structural highlights ==<br />
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This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
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</StructureSection><br />
== References ==<br />
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<div>==LPA1 Receptor (''Homo sapiens'')==<br />
[[Image:General Pic.png|100 px|left|thumb|Figure Legend]]<br />
<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''><br />
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== Function ==<br />
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== Disease ==<br />
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== Pharmacology ==<br />
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== Relevance ==<br />
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== Structural highlights ==<br />
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This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
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</StructureSection><br />
== References ==<br />
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<div>==LPA1 Receptor (''Homo sapiens'')==<br />
[[Image:General Pic.png|100 px|left|thumb|Figure Legend]]<br />
<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''><br />
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== Function ==<br />
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== Disease ==<br />
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== Relevance ==<br />
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== Structural highlights ==<br />
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This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
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</StructureSection><br />
== References ==<br />
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<div>==LPA1 Receptor (''Homo sapiens'')==<br />
[[Image:General Pic.png]]<br />
<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''><br />
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== Function ==<br />
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== Disease ==<br />
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== Relevance ==<br />
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== Structural highlights ==<br />
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This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
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</StructureSection><br />
== References ==<br />
<references/></div>Chandler Mitchell