Sandbox Reserved 1172: Difference between revisions

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=== Key Ligand Interactions ===

[[Image:Amphbindingfinal.png|275 px|right|thumb|Figure 2: Electrostatic illustration of the amphipathic binding pocket of the LPA1 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.]]

The biological ligand of the LPA1 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 LPA1 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 LPA1 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 LPA1 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>

The biological ligand of the LPA1 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 (Figure 3). Four separate interactions with this antagonist of LPA1 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 LPA1 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 LPA1 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>

[[Image:Compare.png|175 px|left|thumb|Figure 3: Structures of LPA and its antagonist, ON7, respectively.]]

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@@ Line 11: / Line 11: @@
 === Key Ligand Interactions ===
 [[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.]]
-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>
+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 (Figure 3).  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>
 [[Image:Compare.png|175 px|left|thumb|Figure 3: Structures of LPA and its antagonist, ON7, respectively.]]