Proteopedia - User contributions [en]

Sandbox reserved 1169

2016-04-19T02:53:38Z

Andrew Koelper:

==Neurotensin Receptor (NTSR1)==
<StructureSection | PDB=4GRV2 | Size =400 | Side=right | scene ='72/727765/Overall_structure/2' | caption='Neurotensin G-Protein Coupled Receptor (PDB Codes [http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV] and [http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE])'>__NoTOC__
== Introduction ==
The neurotensin receptor (NTSR1) belongs to the superfamily of proteins known as [http://proteopedia.org/wiki/index.php/G_protein-coupled_receptor G protein-coupled receptors] (GPCRs) and responds to the 13 amino acid hormone [https://en.wikipedia.org/wiki/Neurotensin neurotensin (NTS)]. Currently around 800 G protein-coupled receptors have been identified and are hypothesized to be responsible for roughly 80% of [https://en.wikipedia.org/wiki/Signal_transduction signal transduction].<ref name="Millar">PMID:20019124</ref> GPCRs are involved in a vast array of physiological processes within the body that range from interactions with [https://en.wikipedia.org/wiki/Dopamine dopamine] to effects on secretion of bile in the intestines.<ref name="Gui">PMID:11208724</ref> <ref name="Binder">PMID:1173461</ref> Due to the vast array of functions that these proteins serve and their high abundance within the body, these proteins have become major drug targets.<ref name="Fang">PMID:23573662</ref>

A critical topic in the understanding of GPCRs is the transition from the inactive to active state. This transition is responsible for the [https://en.wikipedia.org/wiki/Signal_transduction transduction] of a signal from the extracellular to the intracellular space. The transition occurs when a ligand, NTS in the case of NTSR1, binds to the receptor causing a [https://en.wikipedia.org/wiki/Conformational_change conformational change] in the protein that leads to the activation of the intracellular G protein. Currently no crystal structures of the receptor in its unbound, inactive form exist making the transition difficult to study. <ref name="White">PMID:23051748</ref> NTSR1 can be seen in blue and the ligand NTS can be seen in green.
== Neurotensin ==
[https://en.wikipedia.org/wiki/Neurotensin Neurotensin (NTS)] is a 13-[https://en.wikipedia.org/wiki/Amino_acid amino acid] [https://en.wikipedia.org/wiki/Peptide peptide] originally isolated from [https://en.wikipedia.org/w/index.php?title=Bovinae&redirect=no bovine] [https://en.wikipedia.org/wiki/Hypothalamus hypothalamus]. <ref name="Leeman">PMID:4745447</ref> NTS fulfills the roles of both a [https://en.wikipedia.org/wiki/Neurotransmitter neurotransmitter] and a [https://en.wikipedia.org/wiki/Neuromodulation neuromodulator] in the nervous system and a [https://en.wikipedia.org/wiki/Hormone hormone] in the periphery nervous system. NTS is a neuromodulator of dopamine transmission and of anterior [https://en.wikipedia.org/wiki/Pituitary_gland pituitary] hormone secretion. <ref name="Kitabgi">PMID: 20504406</ref> In the periphery of the digestive tract and cardiovascular system, NTS is a [https://en.wikipedia.org/w/index.php?title=Paracrine_signalling&redirect=no paracrine] and [https://en.wikipedia.org/wiki/Endocrine_system endocrine] modulator.<ref name="Mustain">PMID:21124211</ref> Finally, NTS serves as a [https://en.wikipedia.org/wiki/Growth_factor growth factor] for many normal and cancerous cell types. <ref name="Vincent">PMID:10390649</ref>

Only the C-terminal tail of NTS, amino acids 8-13, were resolved in the <scene name='72/721539/Nts8_13/2'>crystal structure</scene>.(PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] Amino acids 8-13 are only resolved because these are the amino acids that interact with NTRS1 to produce the conformational change that is responsible for G-protein activation. The peptide is colored by element: carbon, oxygen, nitrogen.
== Structure ==
=== Overall Structure ===
[[Image:Nuerotensin membrane.jpg |100 px|left|thumb|Figure 1: Neurotensin Incorporation in Membrane. This image depicts the spanning of the membrane made by NTSR1 and illustrates the need for transduction from its extracellular binding site to the intracellular region. (PubMed).]]
Like other G protein-coupled receptors, the neurotensin receptor is composed of 3 distinct regions. An <scene name='72/727765/Overall_structure/5'>extracellular binding site</scene> where neurotensin binds and causes a conformational change of the protein. A region containing <scene name='72/727765/Overall_structure/4'>7 transmembrane alpha helices</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] that transduce the signal from the extracellular side of the cell membrane to the intracellular side. Lastly, an intracellular region, that when activated by a conformational change in the protein, activates a [https://en.wikipedia.org/wiki/G_protein G protein] associated with this receptor. Currently no crystal structures of the inactive form of the neurotensin receptor available. Without a representation of the inactive form, the conformational changes caused by agonist binding are still not completely known.
=== Neurotensin Binding Site ===
Binding of NTS to the binding site on NTSR1 is enriched by <scene name='72/721539/Binding_pocket_surface/4'>charge complementarity</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]between the positive NTS arginine side chains and the [https://en.wikipedia.org/wiki/Electronegativity electronegative] pocket. The protein is colored by charge: negative and positive. Two of NTS's arginine residues are colored blue. In addition, the C-terminus of NTS forms a <scene name='72/721539/Binding_site_charges/4'>salt bridge</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] with Arg328 of NTSR1. Three [https://en.wikipedia.org/wiki/Hydrogen_bond hydrogen bonds] are made between the side chains of NTS and the receptor while most of the interactions are a result of [https://en.wikipedia.org/wiki/Van_der_Waals_force van der Waals] interactions. The binding pocket is partially capped by a <scene name='72/721539/B-hairpin_loop/1'>Β-hairpin loop</scene> at the proximal end of the receptor's N-terminus.<ref name="White"/> The interactions in the binding site cause a wide spread conformational change in the receptor leading to the receptor to adopt an active conformation. This active conformation allows for the activating of the associated intracellular G-protein.
=== Hydrophobic Stacking ===
A major player in the transduction of the extracellular signal to the intracellular G protein is the <scene name='72/727765/Hydrogen_bonding_network/4'>hydrogen bonding network</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]that links the bound hormone with the [https://en.wikipedia.org/wiki/Hydrophobe hydrophobic] core of the neurotensin receptor. The carboxylate of L13 forms a hydrogen bond network with R327, R328, and Y324. The Tyr324, in turn, is brought into an orientation to make the formation of a <scene name='72/727765/Hydrophobic_stacking_4xee/2'>hydrophobic stacking</scene> (PDB Code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE]) network between F358, W321, A157, and F317 possible.<ref name="Krumm">PMID:23051748</ref> The effects that this network has on the activation of the intracellular G-protein was examined by the [https://en.wikipedia.org/wiki/Mutagenesis mutagenesis] of amino acids involved in this network. Mutagenesis of <scene name='72/727765/Overall_structure/12'>A86L</scene>, <scene name='72/727765/Overall_structure/13'>E166A</scene>, <scene name='72/727765/Overall_structure/14'>G125L</scene>, <scene name='72/727765/Overall_structure/15'>L310A</scene>, <scene name='72/727765/Overall_structure/16'>F358A</scene>, and <scene name='72/727765/Overall_structure/17'>V360A</scene> showed that when this interaction was disrupted, the receptor no longer was able to activate the G-protein. <ref name="Krumm"/> This discovery lead to the conclusion that the conformational changes caused by this stacking allows for the signal to be moved from the extracellular binding site through the transmembrane helices of the receptor to the intracellular region activating the G-protein.
== Sodium Binding Pocket ==
Conserved across all class A GPCRs, a <scene name='72/727765/Gw5_na_pocket_final/4'>sodium ion-binding pocket</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] is seen in the middle of TM2 helix. The sodium ion is coordinated with a highly conserved Asp113 and four other oxygen contacts from a combination of water molecules. For G-protein activation to occur, a <scene name='72/721539/4xee_na_binding_pocket/2'>hydrogen bond coordination</scene> (PDB Code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE]) with T156, S362, and N365 of the NPxxY [https://en.wikipedia.org/wiki/Structural_motif motif] must occur. The binding of Na+ within this site disrupts the coordination of the hydrogen bonds and places the receptor in its inactive form. <ref name="Katritch">PMID:24767681</ref>
=== Allosteric Effects ===
Sodium ions are a negative [https://en.wikipedia.org/wiki/Allosteric_regulation allosteric] inhibitor to the binding of the neurotensin [https://en.wikipedia.org/wiki/Agonist agonist] to the binding site on the neurotensin receptor. Sodium's binding causes for the receptor to favor its inactive state. Asp113 of the highly conserved D/RY motif and Asn365 of the highly conserved NPxxY motif form a substantial hydrogen bonding network with T156 and S362.<ref name="Krumm"/> This hydrogen bonding network prevents the incorporation of the sodium ion by collapsing upon itself and filling the sodium binding pocket. Trp321 also works to inhibit the incorporation of the sodium ion by capping off the sodium binding pocket to not allow sodium to enter from the top. Trp321 uses van der Walls interactions to place it in the conformation necessary to block sodium from entering the site. By not allowing for sodium to enter this binding site, the receptor is able to conform to its active state and activate the G-protein that is associated with it.
==Clinical Relevance==
NTSR1 is commonly expressed in various invasive [https://en.wikipedia.org/wiki/Cancer cancer] cell lines making it a promising cancer drug target. It is prevalent in [https://en.wikipedia.org/wiki/Colorectal_cancer colon cancer] [https://en.wikipedia.org/wiki/Adenocarcinoma adenocarcinoma], but is not found in adult colon cell types.<ref name="Valerie">PMID:21903767</ref> NTSR1 is also found in aggressive [https://en.wikipedia.org/wiki/Prostate_cancer prostate cancer] cells, but not [https://en.wikipedia.org/wiki/Epithelium epithelial] prostate cells. In prostate cancer cells, binding of NTS results in [https://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase mitogen-activated protein kinase (PKB)], [https://en.wikipedia.org/wiki/Phosphoinositide_3-kinase phosphoinositide-3 kinase (PI-3K)], [https://en.wikipedia.org/wiki/Epidermal_growth_factor_receptor epidermal growth factor receptor (EGFR)], [https://en.wikipedia.org/wiki/Proto-oncogene_tyrosine-protein_kinase_Src SRC], and [https://en.wikipedia.org/wiki/STAT5 STAT5] phosphorylation.<ref name="Valerie"/> These all result in increased DNA synthesis, [https://en.wikipedia.org/wiki/Cell_growth cell proliferation], and survival. Inhibition of NTSR1 and its downstream signaling represents a target for [https://en.wikipedia.org/wiki/Radiation_therapy radiotherapy], which uses radiation to target malignant cells. [[Image: Meclinerant.jpg |100 px|left|thumb|Meclinerant: An inhibitor of NTSR1 found to enhance selectivity of radiotherapy in cancer treatment (PubMed).]]NTSR1 can be inhibited by agonist [https://en.wikipedia.org/wiki/Meclinertant meclinertant] which inhibits proliferation and prosurvival of cancer cells. Combination treatment of radiation and meclinerant provides selective treatment of cancer cells over normal cells, indicating the need for clinical trials of this approach. <ref name="Kisfalvi">PMID:19679549</ref>

</StructureSection>
== References ==
<references/>

Sandbox reserved 1169

2016-04-19T02:43:29Z

Andrew Koelper:

==Neurotensin Receptor (NTSR1)==
<StructureSection | PDB=4GRV2 | Size =400 | Side=right | scene ='72/727765/Overall_structure/2' | caption='Neurotensin G-Protein Coupled Receptor (PDB Codes [http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV] and [http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE])'>__NoTOC__
== Introduction ==
The neurotensin receptor (NTSR1) belongs to the superfamily of proteins known as [http://proteopedia.org/wiki/index.php/G_protein-coupled_receptor G protein-coupled receptors] (GPCRs) and responds to the 13 amino acid hormone [https://en.wikipedia.org/wiki/Neurotensin neurotensin (NTS)]. Currently around 800 G protein-coupled receptors have been identified and are hypothesized to be responsible for roughly 80% of [https://en.wikipedia.org/wiki/Signal_transduction signal transduction].<ref name="Millar">PMID:20019124</ref> GPCRs are involved in a vast array of physiological processes within the body that range from interactions with [https://en.wikipedia.org/wiki/Dopamine dopamine] to effects on secretion of bile in the intestines.<ref name="Gui">PMID:11208724</ref> <ref name="Binder">PMID:1173461</ref> Due to the vast array of functions that these proteins serve and their high abundance within the body, these proteins have become major drug targets.<ref name="Fang">PMID:23573662</ref>

A critical topic in the understanding of GPCRs is the transition from the inactive to active state. This transition is responsible for the [https://en.wikipedia.org/wiki/Signal_transduction transduction] of a signal from the extracellular to the intracellular space. The transition occurs when a ligand, NTS in the case of NTSR1, binds to the receptor causing a [https://en.wikipedia.org/wiki/Conformational_change conformational change] in the protein that leads to the activation of the intracellular G protein. Currently no crystal structures of the receptor in its unbound, inactive form exist making the transition difficult to study. <ref name="White">PMID:23051748</ref> NTSR1 can be seen in blue and the ligand NTS can be seen in green.
== Neurotensin ==
[https://en.wikipedia.org/wiki/Neurotensin Neurotensin (NTS)] is a 13-[https://en.wikipedia.org/wiki/Amino_acid amino acid] [https://en.wikipedia.org/wiki/Peptide peptide] originally isolated from [https://en.wikipedia.org/w/index.php?title=Bovinae&redirect=no bovine] [https://en.wikipedia.org/wiki/Hypothalamus hypothalamus]. <ref name="Leeman">PMID:4745447</ref> NTS fulfills the roles of both a [https://en.wikipedia.org/wiki/Neurotransmitter neurotransmitter] and a [https://en.wikipedia.org/wiki/Neuromodulation neuromodulator] in the nervous system and a [https://en.wikipedia.org/wiki/Hormone hormone] in the periphery nervous system. NTS is a neuromodulator of dopamine transmission and of anterior [https://en.wikipedia.org/wiki/Pituitary_gland pituitary] hormone secretion. <ref name="Kitabgi">PMID: 20504406</ref> In the periphery of the digestive tract and cardiovascular system, NTS is a [https://en.wikipedia.org/w/index.php?title=Paracrine_signalling&redirect=no paracrine] and [https://en.wikipedia.org/wiki/Endocrine_system endocrine] modulator.<ref name="Mustain">PMID:21124211</ref> Finally, NTS serves as a [https://en.wikipedia.org/wiki/Growth_factor growth factor] for many normal and cancerous cell types. <ref name="Vincent">PMID:10390649</ref>

Only the C-terminal tail of NTS, amino acids 8-13, were resolved in the <scene name='72/721539/Nts8_13/2'>crystal structure</scene>.(PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] Amino acids 8-13 are only resolved because these are the amino acids that interact with NTRS1 to produce the conformational change that is responsible for G-protein activation. The peptide is colored by element: carbon, oxygen, nitrogen.
== Structure ==
=== Overall Structure ===
[[Image:Nuerotensin membrane.jpg |100 px|left|thumb|Figure 1: Neurotensin Incorporation in Membrane. This image depicts the spanning of the membrane made by NTSR1 and illustrates the need for transduction from its extracellular binding site to the intracellular region. (PubMed).]]
Like other G protein-coupled receptors, the neurotensin receptor is composed of 3 distinct regions. An <scene name='72/727765/Overall_structure/5'>extracellular binding site</scene> where neurotensin binds and causes a conformational change of the protein. A region containing <scene name='72/727765/Overall_structure/4'>7 transmembrane alpha helices</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] that transduce the signal from the extracellular side of the cell membrane to the intracellular side. Lastly, an intracellular region, that when activated by a conformational change in the protein, activates a [https://en.wikipedia.org/wiki/G_protein G protein] associated with this receptor. Currently no crystal structures of the inactive form of the neurotensin receptor available. Without a representation of the inactive form, the conformational changes caused by agonist binding are still not completely known.
=== Neurotensin Binding Site ===
Binding of NTS to the binding site on NTSR1 is enriched by <scene name='72/721539/Binding_pocket_surface/4'>charge complementarity</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]between the positive NTS arginine side chains and the [https://en.wikipedia.org/wiki/Electronegativity electronegative] pocket. The protein is colored by charge: negative and positive. Two of NTS's arginine residues are colored blue. In addition, the C-terminus of NTS forms a <scene name='72/721539/Binding_site_charges/4'>salt bridge</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] with Arg328 of NTSR1. Three [https://en.wikipedia.org/wiki/Hydrogen_bond hydrogen bonds] are made between the side chains of NTS and the receptor while most of the interactions are a result of [https://en.wikipedia.org/wiki/Van_der_Waals_force van der Waals] interactions. The binding pocket is partially capped by a <scene name='72/721539/B-hairpin_loop/1'>Β-hairpin loop</scene> at the proximal end of the receptor's N-terminus.<ref name="White"/> The interactions in the binding site cause a wide spread conformational change in the receptor leading to the receptor to adopt an active conformation. This active conformation allows for the activating of the associated intracellular G-protein.
=== Hydrophobic Stacking ===
A major player in the transduction of the extracellular signal to the intracellular G protein is the <scene name='72/727765/Hydrogen_bonding_network/4'>hydrogen bonding network</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]that links the bound hormone with the [https://en.wikipedia.org/wiki/Hydrophobe hydrophobic] core of the neurotensin receptor. The carboxylate of L13 forms a hydrogen bond network with R327, R328, and Y324. The Tyr324, in turn, is brought into an orientation to make the formation of a <scene name='72/727765/Hydrophobic_stacking_4xee/2'>hydrophobic stacking</scene> (PDB Code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE]) network between F358, W321, A157, and F317 possible.<ref name="Krumm">PMID:23051748</ref> The effects that this network has on the activation of the intracellular G-protein was examined by the [https://en.wikipedia.org/wiki/Mutagenesis mutagenesis] of amino acids involved in this network. Mutagenesis of <scene name='72/727765/Overall_structure/6'>A86L</scene>, <scene name='72/727765/Overall_structure/7'>E166A</scene>, <scene name='72/727765/Overall_structure/8'>G125L</scene>, <scene name='72/727765/Overall_structure/9'>L310A</scene>, <scene name='72/727765/Overall_structure/10'>F358A</scene>, and <scene name='72/727765/Overall_structure/11'>V360A</scene> showed that when this interaction was disrupted, the receptor no longer was able to activate the G-protein. <ref name="Krumm"/> This discovery lead to the conclusion that the conformational changes caused by this stacking allows for the signal to be moved from the extracellular binding site through the transmembrane helices of the receptor to the intracellular region activating the G-protein.
== Sodium Binding Pocket ==
Conserved across all class A GPCRs, a <scene name='72/727765/Gw5_na_pocket_final/4'>sodium ion-binding pocket</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] is seen in the middle of TM2 helix. The sodium ion is coordinated with a highly conserved Asp113 and four other oxygen contacts from a combination of water molecules. For G-protein activation to occur, a <scene name='72/721539/4xee_na_binding_pocket/2'>hydrogen bond coordination</scene> (PDB Code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE]) with T156, S362, and N365 of the NPxxY [https://en.wikipedia.org/wiki/Structural_motif motif] must occur. The binding of Na+ within this site disrupts the coordination of the hydrogen bonds and places the receptor in its inactive form. <ref name="Katritch">PMID:24767681</ref>
=== Allosteric Effects ===
Sodium ions are a negative [https://en.wikipedia.org/wiki/Allosteric_regulation allosteric] inhibitor to the binding of the neurotensin [https://en.wikipedia.org/wiki/Agonist agonist] to the binding site on the neurotensin receptor. Sodium's binding causes for the receptor to favor its inactive state. Asp113 of the highly conserved D/RY motif and Asn365 of the highly conserved NPxxY motif form a substantial hydrogen bonding network with T156 and S362.<ref name="Krumm"/> This hydrogen bonding network prevents the incorporation of the sodium ion by collapsing upon itself and filling the sodium binding pocket. Trp321 also works to inhibit the incorporation of the sodium ion by capping off the sodium binding pocket to not allow sodium to enter from the top. Trp321 uses van der Walls interactions to place it in the conformation necessary to block sodium from entering the site. By not allowing for sodium to enter this binding site, the receptor is able to conform to its active state and activate the G-protein that is associated with it.
==Clinical Relevance==
NTSR1 is commonly expressed in various invasive [https://en.wikipedia.org/wiki/Cancer cancer] cell lines making it a promising cancer drug target. It is prevalent in [https://en.wikipedia.org/wiki/Colorectal_cancer colon cancer] [https://en.wikipedia.org/wiki/Adenocarcinoma adenocarcinoma], but is not found in adult colon cell types.<ref name="Valerie">PMID:21903767</ref> NTSR1 is also found in aggressive [https://en.wikipedia.org/wiki/Prostate_cancer prostate cancer] cells, but not [https://en.wikipedia.org/wiki/Epithelium epithelial] prostate cells. In prostate cancer cells, binding of NTS results in [https://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase mitogen-activated protein kinase (PKB)], [https://en.wikipedia.org/wiki/Phosphoinositide_3-kinase phosphoinositide-3 kinase (PI-3K)], [https://en.wikipedia.org/wiki/Epidermal_growth_factor_receptor epidermal growth factor receptor (EGFR)], [https://en.wikipedia.org/wiki/Proto-oncogene_tyrosine-protein_kinase_Src SRC], and [https://en.wikipedia.org/wiki/STAT5 STAT5] phosphorylation.<ref name="Valerie"/> These all result in increased DNA synthesis, [https://en.wikipedia.org/wiki/Cell_growth cell proliferation], and survival. Inhibition of NTSR1 and its downstream signaling represents a target for [https://en.wikipedia.org/wiki/Radiation_therapy radiotherapy], which uses radiation to target malignant cells. [[Image: Meclinerant.jpg |100 px|left|thumb|Meclinerant: An inhibitor of NTSR1 found to enhance selectivity of radiotherapy in cancer treatment (PubMed).]]NTSR1 can be inhibited by agonist [https://en.wikipedia.org/wiki/Meclinertant meclinertant] which inhibits proliferation and prosurvival of cancer cells. Combination treatment of radiation and meclinerant provides selective treatment of cancer cells over normal cells, indicating the need for clinical trials of this approach. <ref name="Kisfalvi">PMID:19679549</ref>

</StructureSection>
== References ==
<references/>

Sandbox reserved 1169

2016-04-18T20:37:13Z

Andrew Koelper:

==Neurotensin Receptor (NTSR1)==
<StructureSection | PDB=4GRV2 | Size =400 | Side=right | scene ='72/727765/Overall_structure/2' | caption='Neurotensin G-Protein Coupled Receptor (PDB Codes [http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV] and [http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE])'>__NoTOC__
== Introduction ==
The neurotensin receptor (NTSR1) belongs to the superfamily of proteins known as [http://proteopedia.org/wiki/index.php/G_protein-coupled_receptor G protein-coupled receptors] (GPCRs) and responds to the 13 amino acid hormone [https://en.wikipedia.org/wiki/Neurotensin neurotensin (NTS)]. Currently around 800 G protein-coupled receptors have been identified and are hypothesized to be responsible for roughly 80% of [https://en.wikipedia.org/wiki/Signal_transduction signal transduction].<ref name="Millar">PMID:20019124</ref> GPCRs are involved in a vast array of physiological processes within the body that range from interactions with [https://en.wikipedia.org/wiki/Dopamine dopamine] to effects on secretion of bile in the intestines.<ref name="Gui">PMID:11208724</ref> <ref name="Binder">PMID:1173461</ref> Due to the vast array of functions that these proteins serve and their high abundance within the body, these proteins have become major drug targets.<ref name="Fang">PMID:23573662</ref>

A critical topic in the understanding of GPCRs is the transition from the inactive to active state. This transition is responsible for the [https://en.wikipedia.org/wiki/Signal_transduction transduction] of a signal from the extracellular to the intracellular space. The transition occurs when a ligand, NTS in the case of NTSR1, binds to the receptor causing a [https://en.wikipedia.org/wiki/Conformational_change conformational change] in the protein that leads to the activation of the intracellular G protein. Currently no crystal structures of the receptor in its unbound, inactive form exist making the transition difficult to study. <ref name="White">PMID:23051748</ref> NTSR1 can be seen in blue and the ligand NTS can be seen in green.
== Neurotensin ==
[https://en.wikipedia.org/wiki/Neurotensin Neurotensin (NTS)] is a 13-[https://en.wikipedia.org/wiki/Amino_acid amino acid] [https://en.wikipedia.org/wiki/Peptide peptide] originally isolated from [https://en.wikipedia.org/w/index.php?title=Bovinae&redirect=no bovine] [https://en.wikipedia.org/wiki/Hypothalamus hypothalamus]. <ref name="Leeman">PMID:4745447</ref> NTS fulfills the roles of both a [https://en.wikipedia.org/wiki/Neurotransmitter neurotransmitter] and a [https://en.wikipedia.org/wiki/Neuromodulation neuromodulator] in the nervous system and a [https://en.wikipedia.org/wiki/Hormone hormone] in the periphery nervous system. NTS is a neuromodulator of dopamine transmission and of anterior [https://en.wikipedia.org/wiki/Pituitary_gland pituitary] hormone secretion. <ref name="Kitabgi">PMID: 20504406</ref> In the periphery of the digestive tract and cardiovascular system, NTS is a [https://en.wikipedia.org/w/index.php?title=Paracrine_signalling&redirect=no paracrine] and [https://en.wikipedia.org/wiki/Endocrine_system endocrine] modulator.<ref name="Mustain">PMID:21124211</ref> Finally, NTS serves as a [https://en.wikipedia.org/wiki/Growth_factor growth factor] for many normal and cancerous cell types. <ref name="Vincent">PMID:10390649</ref>

Only the C-terminal tail of NTS, amino acids 8-13, were resolved in the <scene name='72/721539/Nts8_13/2'>crystal structure</scene>.(PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] Amino acids 8-13 are only resolved because these are the amino acids that interact with NTRS1 to produce the conformational change that is responsible for G-protein activation. The peptide is colored by element: carbon, oxygen, nitrogen.
== Structure ==
=== Overall Structure ===
[[Image:Nuerotensin membrane.jpg |100 px|left|thumb|Figure 1: Neurotensin Incorporation in Membrane. This image depicts the spanning of the membrane made by NTSR1 and illustrates the need for transduction from its extracellular binding site to the intracellular region. (PubMed).]]
Like other G protein-coupled receptors, the neurotensin receptor is composed of 3 distinct regions. An <scene name='72/727765/Overall_structure/5'>extracellular binding site</scene> where neurotensin binds and causes a conformational change of the protein. A region containing <scene name='72/727765/Overall_structure/4'>7 transmembrane alpha helices</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] that transduce the signal from the extracellular side of the cell membrane to the intracellular side. Lastly, an intracellular region, that when activated by a conformational change in the protein, activates a [https://en.wikipedia.org/wiki/G_protein G protein] associated with this receptor. Currently no crystal structures of the inactive form of the neurotensin receptor available. Without a representation of the inactive form, the conformational changes caused by agonist binding are still not completely known.
=== Neurotensin Binding Site ===
Binding of NTS to the binding site on NTSR1 is enriched by <scene name='72/721539/Binding_pocket_surface/4'>charge complementarity</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]between the positive NTS arginine side chains and the [https://en.wikipedia.org/wiki/Electronegativity electronegative] pocket. The protein is colored by charge: negative and positive. Two of NTS's arginine residues are colored blue. In addition, the C-terminus of NTS forms a <scene name='72/721539/Binding_site_charges/4'>salt bridge</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] with Arg328 of NTSR1. Three [https://en.wikipedia.org/wiki/Hydrogen_bond hydrogen bonds] are made between the side chains of NTS and the receptor while most of the interactions are a result of [https://en.wikipedia.org/wiki/Van_der_Waals_force van der Waals] interactions. The binding pocket is partially capped by a <scene name='72/721539/B-hairpin_loop/1'>Β-hairpin loop</scene> at the proximal end of the receptor's N-terminus.<ref name="White"/> The interactions in the binding site cause a wide spread conformational change in the receptor leading to the receptor to adopt an active conformation. This active conformation allows for the activating of the associated intracellular G-protein.
=== Hydrophobic Stacking ===
A major player in the transduction of the extracellular signal to the intracellular G protein is the <scene name='72/727765/Hydrogen_bonding_network/4'>hydrogen bonding network</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]that links the bound hormone with the [https://en.wikipedia.org/wiki/Hydrophobe hydrophobic] core of the neurotensin receptor. The carboxylate of L13 forms a hydrogen bond network with R327, R328, and Y324. The Tyr324, in turn, is brought into an orientation to make the formation of a <scene name='72/727765/Hydrophobic_stacking_4xee/2'>hydrophobic stacking</scene> (PDB Code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE]) network between F358, W321, A157, and F317 possible.<ref name="Krumm">PMID:23051748</ref> The effects that this network has on the activation of the intracellular G-protein was examined by the [https://en.wikipedia.org/wiki/Mutagenesis mutagenesis] of amino acids involved in this network. Mutagenesis of A86L, E166A, G125A, L310A, F358A, and V360A showed that when this interaction was disrupted, the receptor no longer was able to activate the G-protein. <ref name="Krumm"/> This discovery lead to the conclusion that the conformational changes caused by this stacking allows for the signal to be moved from the extracellular binding site through the transmembrane helices of the receptor to the intracellular region activating the G-protein.
== Sodium Binding Pocket ==
Conserved across all class A GPCRs, a <scene name='72/727765/Gw5_na_pocket_final/4'>sodium ion-binding pocket</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] is seen in the middle of TM2 helix. The sodium ion is coordinated with a highly conserved Asp113 and four other oxygen contacts from a combination of water molecules. For G-protein activation to occur, a <scene name='72/721539/4xee_na_binding_pocket/2'>hydrogen bond coordination</scene> (PDB Code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE]) with T156, S362, and N365 of the NPxxY [https://en.wikipedia.org/wiki/Structural_motif motif] must occur. The binding of Na+ within this site disrupts the coordination of the hydrogen bonds and places the receptor in its inactive form. <ref name="Katritch">PMID:24767681</ref>
=== Allosteric Effects ===
Sodium ions are a negative [https://en.wikipedia.org/wiki/Allosteric_regulation allosteric] inhibitor to the binding of the neurotensin [https://en.wikipedia.org/wiki/Agonist agonist] to the binding site on the neurotensin receptor. Sodium's binding causes for the receptor to favor its inactive state. Asp113 of the highly conserved D/RY motif and Asn365 of the highly conserved NPxxY motif form a substantial hydrogen bonding network with T156 and S362.<ref name="Krumm"/> This hydrogen bonding network prevents the incorporation of the sodium ion by collapsing upon itself and filling the sodium binding pocket. Trp321 also works to inhibit the incorporation of the sodium ion by capping off the sodium binding pocket to not allow sodium to enter from the top. Trp321 uses van der Walls interactions to place it in the conformation necessary to block sodium from entering the site. By not allowing for sodium to enter this binding site, the receptor is able to conform to its active state and activate the G-protein that is associated with it.
==Clinical Relevance==
NTSR1 is commonly expressed in various invasive [https://en.wikipedia.org/wiki/Cancer cancer] cell lines making it a promising cancer drug target. It is prevalent in [https://en.wikipedia.org/wiki/Colorectal_cancer colon cancer] [https://en.wikipedia.org/wiki/Adenocarcinoma adenocarcinoma], but is not found in adult colon cell types.<ref name="Valerie">PMID:21903767</ref> NTSR1 is also found in aggressive [https://en.wikipedia.org/wiki/Prostate_cancer prostate cancer] cells, but not [https://en.wikipedia.org/wiki/Epithelium epithelial] prostate cells. In prostate cancer cells, binding of NTS results in [https://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase mitogen-activated protein kinase (PKB)], [https://en.wikipedia.org/wiki/Phosphoinositide_3-kinase phosphoinositide-3 kinase (PI-3K)], [https://en.wikipedia.org/wiki/Epidermal_growth_factor_receptor epidermal growth factor receptor (EGFR)], [https://en.wikipedia.org/wiki/Proto-oncogene_tyrosine-protein_kinase_Src SRC], and [https://en.wikipedia.org/wiki/STAT5 STAT5] phosphorylation.<ref name="Valerie"/> These all result in increased DNA synthesis, [https://en.wikipedia.org/wiki/Cell_growth cell proliferation], and survival. Inhibition of NTSR1 and its downstream signaling represents a target for [https://en.wikipedia.org/wiki/Radiation_therapy radiotherapy], which uses radiation to target malignant cells. [[Image: Meclinerant.jpg |100 px|left|thumb|Meclinerant: An inhibitor of NTSR1 found to enhance selectivity of radiotherapy in cancer treatment (PubMed).]]NTSR1 can be inhibited by agonist [https://en.wikipedia.org/wiki/Meclinertant meclinertant] which inhibits proliferation and prosurvival of cancer cells. Combination treatment of radiation and meclinerant provides selective treatment of cancer cells over normal cells, indicating the need for clinical trials of this approach. <ref name="Kisfalvi">PMID:19679549</ref>

</StructureSection>
== References ==
<references/>

Sandbox reserved 1169

2016-04-17T23:16:30Z

Andrew Koelper:

==Neurotensin Receptor (NTSR1)==
<StructureSection | PDB=4GRV2 | Size =500 | Side=right | scene ='72/727765/Overall_structure/2' | caption='Neurotensin G-Protein Coupled Receptor (PDB Codes [http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV] and [http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE])'>__NoTOC__
== Introduction ==
The neurotensin receptor (NTSR1) belongs to the superfamily of proteins known as [http://proteopedia.org/wiki/index.php/G_protein-coupled_receptor G protein-coupled receptors] (GPCRs) and responds to the 13 amino acid hormone [https://en.wikipedia.org/wiki/Neurotensin neurotensin (NTS)]. Currently around 800 G protein-coupled receptors have been identified and are hypothesized to be responsible for roughly 80% of [https://en.wikipedia.org/wiki/Signal_transduction signal transduction].<ref name="Millar">PMID:20019124</ref> GPCRs are involved in a vast array of physiological processes within the body that range from interactions with [https://en.wikipedia.org/wiki/Dopamine dopamine] to effects on secretion of bile in the intestines.<ref name="Gui">PMID:11208724</ref> <ref name="Binder">PMID:1173461</ref> Due to the vast array of functions that these proteins serve and their high abundance within the body, these proteins have become major drug targets.<ref name="Fang">PMID:23573662</ref>

A critical topic in the understanding of GPCRs is the transition from the inactive to active state. This transition is responsible for the [https://en.wikipedia.org/wiki/Signal_transduction transduction] of a signal from the extracellular to the intracellular space. The transition occurs when a ligand, NTS in the case of NTSR1, binds to the receptor causing a [https://en.wikipedia.org/wiki/Conformational_change conformational change] in the protein that leads to the activation of the intracellular G protein. Currently no crystal structures of the receptor in its unbound, inactive form exist making the transition more difficult to study. NTSR1 can be seen in blue and the ligand NTS can be seen in green.<ref name="White">PMID:23051748</ref>
== Neurotensin ==
[https://en.wikipedia.org/wiki/Neurotensin Neurotensin (NTS)] is a 13-amino acid peptide originally isolated from [https://en.wikipedia.org/w/index.php?title=Bovinae&redirect=no bovine] [https://en.wikipedia.org/wiki/Hypothalamus hypothalamus]. NTS fulfills the roles of both a [https://en.wikipedia.org/wiki/Neurotransmitter neurotransmitter] and a [https://en.wikipedia.org/wiki/Neuromodulation neuromodulator] in the nervous system and a [https://en.wikipedia.org/wiki/Hormone hormone] in the periphery nervous system. NTS is a neuromodulator of dopamine transmission and of anterior [https://en.wikipedia.org/wiki/Pituitary_gland pituitary] hormone secretion. In the periphery of the digestive tract and cardiovascular system, NTS is a [https://en.wikipedia.org/w/index.php?title=Paracrine_signalling&redirect=no paracrine] and [https://en.wikipedia.org/wiki/Endocrine_system endocrine] modulator. Finally, NTS serves as a [https://en.wikipedia.org/wiki/Growth_factor growth factor] for many normal and cancerous cell types. <ref name="Vincent">PMID:10390649</ref>

Only the C-terminal tail of NTS, amino acids 8-13, were resolved in the <scene name='72/721539/Nts8_13/2'>crystal structure</scene>.(PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]The peptide is colored by element: carbon, oxygen, nitrogen.
== Structure ==
=== Overall Structure ===
[[Image:Nuerotensin membrane.jpg |100 px|left|thumb|Figure 1: Neurotensin Incorporation in Membrane ]]
Like other G protein-coupled receptors, the neurotensin receptor is composed of 3 distinct regions. An extracellular binding site where neurotensin binds and causes a conformational change of the protein. A region containing <scene name='72/727765/Overall_structure/4'>7 transmembrane alpha helices</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] that transduce the signal from the extracellular side of the cell membrane to the intracellular side. Each helix is colored differently for easy identification. Lastly, an intracellular region that when activated by a conformational change in the protein activates a [https://en.wikipedia.org/wiki/G_protein G protein] associated with this receptor. Currently no crystal structures of the inactive form of the neurotensin receptor available. Without a representation of the inactive form, the conformational changes caused by agonist binding are still not completely known.
=== Neurotensin Binding Site ===
Binding of NTS to the binding site is enriched by <scene name='72/721539/Binding_pocket_surface/4'>charge complementarity</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]between the positive NTS arginine side chains and the [https://en.wikipedia.org/wiki/Electronegativity electronegative] pocket. The protein is colored by charge: negative and positive. Two of NTS's arginine residues are colored blue. In addition, the C-terminus of NTS forms a <scene name='72/721539/Binding_site_charges/4'>salt bridge</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] with R328 of NTSR1. Three [https://en.wikipedia.org/wiki/Hydrogen_bond hydrogen bonds] are made between the side chains of NTS and the receptor. Most of the interactions are [https://en.wikipedia.org/wiki/Van_der_Waals_force van der Waals] interactions. The binding pocket is partially capped by a <scene name='72/721539/B-hairpin_loop/1'>Β-hairpin loop</scene> at the proximal end of the receptor protein's N-terminus.<ref name="White"/>
=== Hydrophobic Stacking ===
A major player in the transduction of the extracellular signal to the intracellular G protein is the <scene name='72/727765/Hydrogen_bonding_network/4'>hydrogen bonding network</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]that links the bound hormone with the [https://en.wikipedia.org/wiki/Hydrophobe hydrophobic] core of the neurotensin receptor. The carboxylate of L13 forms a hydrogen bond network with R327, R328, and Y324. The Y324, in turn, is brought into an orientation to make the formation of a <scene name='72/727765/Hydrophobic_stacking_4xee/2'>hydrophobic stacking</scene> (PDB Code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE]) network between F358, W321, A157, and F317 possible.<ref name="Krumm">PMID:23051748</ref> The conformational changes caused by this stacking allows for the signal to be moved from the extracellular binding site through the transmembrane helices of the receptor to the intracellular region activating the G protein.
== Sodium Binding Pocket ==
Conserved across all class A GPCRs, a <scene name='72/727765/Gw5_na_pocket_final/4'>sodium ion-binding pocket</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] is seen in the middle of TM2 helix. The ion is coordinated with a highly conserved D2.50 and four other contacts with oxygen atoms. Some of these oxygen atoms are sourced from water molecules. In order for G-protein activation, a <scene name='72/721539/4xee_na_binding_pocket/2'>hydrogen bond coordination</scene> (PDB Code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE]) with T3.39, S7.46 ,N7.49 of the NPxxY [https://en.wikipedia.org/wiki/Structural_motif motif], prevents the coordination of a Na+. <ref name="Krumm"/><ref name="Katritch">PMID:24767681</ref>
=== Allosteric Effects ===
Sodium ions are a negative [https://en.wikipedia.org/wiki/Allosteric_regulation allosteric] inhibitor to the binding of the neurotensin [https://en.wikipedia.org/wiki/Agonist agonist] to the binding site on the neurotensin receptor. D113 of the highly conserved D/RY motif and N365 of the highly conserved NPxxY motif form a substantial hydrogen bonding network with T156 and S362.<ref name="Krumm"/> This hydrogen bonding network prevents the incorporation of the sodium ion by collapsing upon itself and therefore filling the sodium binding pocket. W321 also works to inhibit the incorporation of the sodium ion by capping off the sodium binding pocket to not allow sodium to enter from the top. W321 uses van der Walls interactions with other amino acids in the binding pocket to place it in the conformation necessary to complete this task.
==Clinical Relevance==
NTSR1 is commonly expressed in various invasive [https://en.wikipedia.org/wiki/Cancer cancer] cell lines. It is prevalent in the [https://en.wikipedia.org/wiki/Colorectal_cancer colon cancer] [https://en.wikipedia.org/wiki/Adenocarcinoma adenocarcinoma], but is not found in adult colon cell types. NTSR1 is also found in aggressive [https://en.wikipedia.org/wiki/Prostate_cancer prostate cancer] cells, but not [https://en.wikipedia.org/wiki/Epithelium epithelial] prostate cells. In prostate cancer cells, binding of the NTS results in [https://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase mitogen-activated protein kinase (PKB)], [https://en.wikipedia.org/wiki/Phosphoinositide_3-kinase phosphoinositide-3 kinase (PI-3K)], [https://en.wikipedia.org/wiki/Epidermal_growth_factor_receptor epidermal growth factor receptor (EGFR)], [https://en.wikipedia.org/wiki/Proto-oncogene_tyrosine-protein_kinase_Src SRC], and [https://en.wikipedia.org/wiki/STAT5 STAT5] phosphorylation. These all result in increased DNA sythesis, [https://en.wikipedia.org/wiki/Cell_growth cell proliferation], and survival. Inhibition of NTSR1 and its downstream signaling represents a target for [https://en.wikipedia.org/wiki/Radiation_therapy radiotherapy]. [[Image: Meclinerant.jpg |100 px|left|thumb|Meclinerant]]NTSR1 can be inhibited by agonist [https://en.wikipedia.org/wiki/Meclinertant meclinertant] which has shown evidence for the inhibition of proliferation and prosurvival of cancer cells. Treatment of radiation and meclinerant has shown to provide selective treatment of cancer cells over normal cells, indicating the need for clinical trials of this approach. <ref name="Valerie">PMID:21903767</ref> <ref name="Kisfalvi">PMID:19679549</ref>

</StructureSection>
== References ==
<references/>

Sandbox reserved 1169

2016-04-17T23:12:38Z

Andrew Koelper:

==Neurotensin Receptor (NTSR1)==
<StructureSection | PDB=4GRV2 | Size =500 | Side=right | scene ='72/727765/Overall_structure/2' | caption='Neurotensin G-Protein Coupled Receptor (PDB Codes [http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV] and [http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE])'>__NoTOC__
== Introduction ==
The neurotensin receptor (NTSR1) belongs to the superfamily of proteins known as [http://proteopedia.org/wiki/index.php/G_protein-coupled_receptor G protein-coupled receptors] (GPCRs) and responds to the 13 amino acid hormone [https://en.wikipedia.org/wiki/Neurotensin neurotensin (NTS)]. Currently around 800 G protein-coupled receptors have been identified and are hypothesized to be responsible for roughly 80% of [https://en.wikipedia.org/wiki/Signal_transduction signal transduction].<ref name="Millar">PMID:20019124</ref> GPCRs are involved in a vast array of physiological processes within the body that range from interactions with [https://en.wikipedia.org/wiki/Dopamine dopamine] to effects on secretion of bile in the intestines.<ref name="Gui">PMID:11208724</ref> <ref name="Binder">PMID:1173461</ref> Due to the vast array of functions that these proteins serve and their high abundance within the body, these proteins have become major drug targets.<ref name="Fang">PMID:23573662</ref>

A critical topic in the understanding of GPCRs is the transition from the inactive to active state. This transition is responsible for the [https://en.wikipedia.org/wiki/Signal_transduction transduction] of a signal from the extracellular to the intracellular space. The transition occurs when a ligand, NTS in the case of NTSR1, binds to the receptor causing a [https://en.wikipedia.org/wiki/Conformational_change conformational change] in the protein that leads to the activation of the intracellular G protein. Currently no crystal structures of the receptor in its unbound, inactive form exist making the transition more difficult to study. NTSR1 can be seen in blue and the ligand NTS can be seen in green.<ref name="White">PMID:23051748</ref>
== Neurotensin ==
[https://en.wikipedia.org/wiki/Neurotensin Neurotensin (NTS)] is a 13-amino acid peptide originally isolated from [https://en.wikipedia.org/w/index.php?title=Bovinae&redirect=no bovine] [https://en.wikipedia.org/wiki/Hypothalamus hypothalamus]. NTS fulfills the roles of both a [https://en.wikipedia.org/wiki/Neurotransmitter neurotransmitter] and a [https://en.wikipedia.org/wiki/Neuromodulation neuromodulator] in the nervous system and a [https://en.wikipedia.org/wiki/Hormone hormone] in the periphery nervous system. NTS is a neuromodulator of dopamine transmission and of anterior [https://en.wikipedia.org/wiki/Pituitary_gland pituitary] hormone secretion. In the periphery of the digestive tract and cardiovascular system, NTS is a [https://en.wikipedia.org/w/index.php?title=Paracrine_signalling&redirect=no paracrine] and [https://en.wikipedia.org/wiki/Endocrine_system endocrine] modulator. Finally, NTS serves as a [https://en.wikipedia.org/wiki/Growth_factor growth factor] for many normal and cancerous cell types. <ref name="Vincent">PMID:10390649</ref>

Only the C-terminal tail of NTS, amino acids 8-13, were resolved in the <scene name='72/721539/Nts8_13/2'>crystal structure</scene>.(PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]The peptide is colored by element: carbon, oxygen, nitrogen.
== Structure ==
=== Overall Structure ===
[[Image:Nuerotensin membrane.jpg |100 px|left|thumb|Figure 1: Neurotensin Incorporation in Membrane ]]
Like other G protein-coupled receptors, the neurotensin receptor is composed of 3 distinct regions. An extracellular binding site where neurotensin binds and causes a conformational change of the protein. A region containing <scene name='72/727765/Overall_structure/4'>7 transmembrane alpha helices</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] that transduce the signal from the extracellular side of the cell membrane to the intracellular side. Each helix is colored differently for easy identification. Lastly, an intracellular region that when activated by a conformational change in the protein activates a [https://en.wikipedia.org/wiki/G_protein G protein] associated with this receptor. Currently no crystal structures of the inactive form of the neurotensin receptor available. Without a representation of the inactive form, the conformational changes caused by agonist binding are still not completely known.
=== Neurotensin Binding Site ===
Binding of NTS to the binding site is enriched by <scene name='72/721539/Binding_pocket_surface/4'>charge complementarity</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]between the positive NTS arginine side chains and the [https://en.wikipedia.org/wiki/Electronegativity electronegative] pocket. The protein is colored by charge: negative and positive. Two of NTS's arginine residues are colored blue. In addition, the C-terminus of NTS forms a <scene name='72/721539/Binding_site_charges/4'>salt bridge</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] with R328 of NTSR1. Three [https://en.wikipedia.org/wiki/Hydrogen_bond hydrogen bonds] are made between the side chains of NTS and the receptor. Most of the interactions are [https://en.wikipedia.org/wiki/Van_der_Waals_force van der Waals] interactions. The binding pocket is partially capped by a <scene name='72/721539/B-hairpin_loop/1'>Β-hairpin loop</scene> at the proximal end of the receptor protein's N-terminus.<ref name="White"/>
=== Hydrophobic Stacking ===
A major player in the transduction of the extracellular signal to the intracellular G protein is the <scene name='72/727765/Hydrogen_bonding_network/4'>hydrogen bonding network</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]that links the bound hormone with the [https://en.wikipedia.org/wiki/Hydrophobe hydrophobic] core of the neurotensin receptor. The carboxylate of L13 forms a hydrogen bond network with R327, R328, and Y324. The Y324, in turn, is brought into an orientation to make the formation of a <scene name='72/727765/Hydrophobic_stacking_4xee/2'>hydrophobic stacking</scene> (PDB Code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE]) network between F358, W321, A157, and F317 possible.<ref name="Krumm">PMID:23051748</ref> The conformational changes caused by this stacking allows for the signal to be moved from the extracellular binding site through the transmembrane helices of the receptor to the intracellular region activating the G protein.
== Sodium Binding Pocket ==
Conserved across all class A GPCRs, a <scene name='72/727765/Gw5_na_pocket_final/4'>sodium ion-binding pocket</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] is seen in the middle of TM2 helix. The ion is coordinated with a highly conserved D2.50 and four other contacts with oxygen atoms. Some of these oxygen atoms are sourced from water molecules. In order for G-protein activation, a <scene name='72/721539/4xee_na_binding_pocket/2'>hydrogen bond coordination</scene> (PDB Code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE]) with T3.39, S7.46 ,N7.49 of the NPxxY [https://en.wikipedia.org/wiki/Structural_motif motif], prevents the coordination of a Na+. <ref name="Krumm"/><ref name="Katritch">PMID:24767681</ref>
=== Allosteric Effects ===
Sodium ions are a negative [https://en.wikipedia.org/wiki/Allosteric_regulation allosteric] inhibitor to the binding of the neurotensin [https://en.wikipedia.org/wiki/Agonist agonist] to the binding site on the neurotensin receptor. D113 of the highly conserved D/RY motif and N365 of the highly conserved NPxxY motif form a substantial hydrogen bonding network with T156 and S362.<ref name="Krumm"/> This hydrogen bonding network prevents the incorporation of the sodium ion by collapsing upon itself and therefor filling the sodium binding pocket. W321 also works to inhibit the incorporation of the sodium ion by capping off the sodium binding pocket to not allow sodium to enter from the top. W321 uses van der Walls interactions with other amino acids in the binding pocket to place it in the conformation necessary to complete this task.
==Clinical Relevance==
NTSR1 is commonly expressed in various invasive [https://en.wikipedia.org/wiki/Cancer cancer] cell lines. It is prevalent in the [https://en.wikipedia.org/wiki/Colorectal_cancer colon cancer] [https://en.wikipedia.org/wiki/Adenocarcinoma adenocarcinoma], but is not found in adult colon cell types. NTSR1 is also found in aggressive [https://en.wikipedia.org/wiki/Prostate_cancer prostate cancer] cells, but not [https://en.wikipedia.org/wiki/Epithelium epithelial] prostate cells. In prostate cancer cells, binding of the NTS results in [https://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase mitogen-activated protein kinase (PKB)], [https://en.wikipedia.org/wiki/Phosphoinositide_3-kinase phosphoinositide-3 kinase (PI-3K)], [https://en.wikipedia.org/wiki/Epidermal_growth_factor_receptor epidermal growth factor receptor (EGFR)], [https://en.wikipedia.org/wiki/Proto-oncogene_tyrosine-protein_kinase_Src SRC], and [https://en.wikipedia.org/wiki/STAT5 STAT5] phosphorylation. These all result in increased DNA sythesis, [https://en.wikipedia.org/wiki/Cell_growth cell proliferation], and survival. Inhibition of NTSR1 and its downstream signaling represents a target for [https://en.wikipedia.org/wiki/Radiation_therapy radiotherapy]. [[Image: Meclinerant.jpg |100 px|left|thumb|Meclinerant]]NTSR1 can be inhibited by agonist [https://en.wikipedia.org/wiki/Meclinertant meclinertant] which has shown evidence for the inhibition of proliferation and prosurvival of cancer cells. Treatment of radiation and meclinerant has shown to provide selective treatment of cancer cells over normal cells, indicating the need for clinical trials of this approach. <ref name="Valerie">PMID:21903767</ref> <ref name="Kisfalvi">PMID:19679549</ref>

</StructureSection>
== References ==
<references/>

Sandbox reserved 1169

2016-04-17T23:04:40Z

Andrew Koelper:

==Neurotensin Receptor (NTSR1)==
<StructureSection | PDB=4GRV2 | Size =500 | Side=right | scene ='72/727765/Overall_structure/2' | caption='Neurotensin G-Protein Coupled Receptor (PDB Codes [http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV] and [http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE])'>__NoTOC__
== Introduction ==
The neurotensin receptor (NTSR1) belongs to the superfamily of proteins known as [http://proteopedia.org/wiki/index.php/G_protein-coupled_receptor G protein-coupled receptors] (GPCRs) and responds to the 13 amino acid hormone [https://en.wikipedia.org/wiki/Neurotensin neurotensin (NTS)]. Currently around 800 G protein-coupled receptors have been identified and are hypothesized to be responsible for roughly 80% of [https://en.wikipedia.org/wiki/Signal_transduction signal transduction].<ref name="Millar">PMID:20019124</ref> GPCRs are involved in a vast array of physiological processes within the body that range from interactions with [https://en.wikipedia.org/wiki/Dopamine dopamine] to effects on secretion of bile in the intestines.<ref name="Gui">PMID:11208724</ref> <ref name="Binder">PMID:1173461</ref> Due to the vast array of functions that these proteins serve and their high abundance within the body, these proteins have become major drug targets.<ref name="Fang">PMID:23573662</ref>

A critical topic in the understanding of GPCRs is the transition from the inactive to active state. This transition is responsible for the [https://en.wikipedia.org/wiki/Signal_transduction transduction] of a signal from the extracellular to the intracellular space. The transition occurs when a ligand, NTS in the case of NTSR1, binds to the receptor causing a [https://en.wikipedia.org/wiki/Conformational_change conformational change] in the protein that leads to the activation of the intracellular G protein. Currently no crystal structures of the receptor in its unbound, inactive form exist making the transition more difficult to study. NTSR1 can be seen in blue and the ligand NTS can be seen in green.<ref name="White">PMID:23051748</ref>
== Neurotensin ==
[https://en.wikipedia.org/wiki/Neurotensin Neurotensin (NTS)] is a 13-amino acid peptide originally isolated from [https://en.wikipedia.org/w/index.php?title=Bovinae&redirect=no bovine] [https://en.wikipedia.org/wiki/Hypothalamus hypothalamus]. NTS fulfills the roles of both a [https://en.wikipedia.org/wiki/Neurotransmitter neurotransmitter] and a [https://en.wikipedia.org/wiki/Neuromodulation neuromodulator] in the nervous system and a [https://en.wikipedia.org/wiki/Hormone hormone] in the periphery nervous system. NTS is a neuromodulator of dopamine transmission and of anterior [https://en.wikipedia.org/wiki/Pituitary_gland pituitary] hormone secretion. In the periphery of the digestive tract and cardiovascular system, NTS is a [https://en.wikipedia.org/w/index.php?title=Paracrine_signalling&redirect=no paracrine] and [https://en.wikipedia.org/wiki/Endocrine_system endocrine] modulator. Finally, NTS serves as a [https://en.wikipedia.org/wiki/Growth_factor growth factor] for many normal and cancerous cell types. <ref name="Vincent">PMID:10390649</ref>

Only the C-terminal tail of NTS, amino acids 8-13, were resolved in the <scene name='72/721539/Nts8_13/2'>crystal structure</scene>.(PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]The peptide is colored by element: carbon, oxygen, nitrogen.
== Structure ==
=== Overall Structure ===
[[Image:Nuerotensin membrane.jpg |100 px|left|thumb|Figure 1: Neurotensin Incorporation in Membrane ]]
Like other G protein-coupled receptors, the neurotensin receptor is composed of 3 distinct regions. An extracellular binding site where neurotensin binds and causes a conformational change of the protein. A region containing <scene name='72/727765/Overall_structure/4'>7 transmembrane alpha helices</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] that transduce the signal from the extracellular side of the cell membrane to the intracellular side. Each helix is colored differently for easy identification. Lastly, an intracellular region that when activated by a conformational change in the protein activates a [https://en.wikipedia.org/wiki/G_protein G protein] associated with this receptor. Currently no crystal structures of the inactive form of the neurotensin receptor available. Without a representation of the inactive form, the conformational changes caused by agonist binding are still not completely known.
=== Neurotensin Binding Site ===
Binding of NTS to the binding site is enriched by <scene name='72/721539/Binding_pocket_surface/4'>charge complementarity</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]between the positive NTS arginine side chains and the [https://en.wikipedia.org/wiki/Electronegativity electronegative] pocket. The protein is colored by charge: negative and positive. Two of NTS's arginine residues are colored blue. In addition, the C-terminus forms a <scene name='72/721539/Binding_site_charges/4'>salt bridge</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] with R328. Only three out of eight [https://en.wikipedia.org/wiki/Hydrogen_bond hydrogen bonds] are made between the side chains of NTS and the receptor. Most of the interactions are [https://en.wikipedia.org/wiki/Van_der_Waals_force van der Waals] interactions. The binding pocket is partially capped by a <scene name='72/721539/B-hairpin_loop/1'>Β-hairpin loop</scene> at the proximal end of the receptor protein's N-terminus.<ref name="White"/>
=== Hydrophobic Stacking ===
A major player in the transduction of the extracellular signal to the intracellular G protein is the <scene name='72/727765/Hydrogen_bonding_network/4'>hydrogen bonding network</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]that links the bound hormone with the [https://en.wikipedia.org/wiki/Hydrophobe hydrophobic] core of the neurotensin receptor. The carboxylate of L13 forms a hydrogen bond network with R327, R328, and Y324. The Y324, in turn, is brought into an orientation to make the formation of a <scene name='72/727765/Hydrophobic_stacking_4xee/2'>hydrophobic stacking</scene> (PDB Code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE]) network between F358, W321, A157, and F317 possible.<ref name="Krumm">PMID:23051748</ref> The conformational changes caused by this stacking allows for the signal to be moved from the extracellular binding site through the transmembrane helices of the receptor to the intracellular region activating the G protein.
== Sodium Binding Pocket ==
Conserved across all class A GPCRs, a <scene name='72/727765/Gw5_na_pocket_final/4'>sodium ion-binding pocket</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] is seen in the middle of TM2 helix. The ion is coordinated with a highly conserved D2.50 and four other contacts with oxygen atoms. Some of these oxygen atoms are sourced from water molecules. In order for G-protein activation, a <scene name='72/721539/4xee_na_binding_pocket/2'>hydrogen bond coordination</scene> (PDB Code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE]) with T3.39, S7.46 ,N7.49 of the NPxxY [https://en.wikipedia.org/wiki/Structural_motif motif], prevents the coordination of a Na+. <ref name="Krumm"/><ref name="Katritch">PMID:24767681</ref>
=== Allosteric Effects ===
Sodium ions are a negative [https://en.wikipedia.org/wiki/Allosteric_regulation allosteric] inhibitor to the binding of the neurotensin [https://en.wikipedia.org/wiki/Agonist agonist] to the binding site on the neurotensin receptor. D113 of the highly conserved D/RY motif and N365 of the highly conserved NPxxY motif form a substantial hydrogen bonding network with T156 and S362.<ref name="Krumm"/> This hydrogen bonding network prevents the incorporation of the sodium ion by collapsing upon itself and therefor filling the sodium binding pocket. W321 also works to inhibit the incorporation of the sodium ion by capping off the sodium binding pocket to not allow sodium to enter from the top. W321 uses van der Walls interactions with other amino acids in the binding pocket to place it in the conformation necessary to complete this task.
==Clinical Relevance==
NTSR1 is commonly expressed in various invasive [https://en.wikipedia.org/wiki/Cancer cancer] cell lines. It is prevalent in the [https://en.wikipedia.org/wiki/Colorectal_cancer colon cancer] [https://en.wikipedia.org/wiki/Adenocarcinoma adenocarcinoma], but is not found in adult colon cell types. NTSR1 is also found in aggressive [https://en.wikipedia.org/wiki/Prostate_cancer prostate cancer] cells, but not [https://en.wikipedia.org/wiki/Epithelium epithelial] prostate cells. In prostate cancer cells, binding of the NTS results in [https://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase mitogen-activated protein kinase (PKB)], [https://en.wikipedia.org/wiki/Phosphoinositide_3-kinase phosphoinositide-3 kinase (PI-3K)], [https://en.wikipedia.org/wiki/Epidermal_growth_factor_receptor epidermal growth factor receptor (EGFR)], [https://en.wikipedia.org/wiki/Proto-oncogene_tyrosine-protein_kinase_Src SRC], and [https://en.wikipedia.org/wiki/STAT5 STAT5] phosphorylation. These all result in increased DNA sythesis, [https://en.wikipedia.org/wiki/Cell_growth cell proliferation], and survival. Inhibition of NTSR1 and its downstream signaling represents a target for [https://en.wikipedia.org/wiki/Radiation_therapy radiotherapy]. [[Image: Meclinerant.jpg |100 px|left|thumb|Meclinerant]]NTSR1 can be inhibited by agonist [https://en.wikipedia.org/wiki/Meclinertant meclinertant] which has shown evidence for the inhibition of proliferation and prosurvival of cancer cells. Treatment of radiation and meclinerant has shown to provide selective treatment of cancer cells over normal cells, indicating the need for clinical trials of this approach. <ref name="Valerie">PMID:21903767</ref> <ref name="Kisfalvi">PMID:19679549</ref>

</StructureSection>
== References ==
<references/>

Sandbox reserved 1169

2016-04-17T23:00:12Z

Andrew Koelper:

==Neurotensin Receptor (NTSR1)==
<StructureSection | PDB=4GRV2 | Size =500 | Side=right | scene ='72/727765/Overall_structure/2' | caption='Neurotensin G-Protein Coupled Receptor (PDB Codes [http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV] and [http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE])'>__NoTOC__
== Introduction ==
The neurotensin receptor (NTSR1) belongs to the superfamily of proteins known as [http://proteopedia.org/wiki/index.php/G_protein-coupled_receptor G protein-coupled receptors] (GPCRs) and responds to the 13 amino acid hormone [https://en.wikipedia.org/wiki/Neurotensin neurotensin (NTS)]. Currently around 800 G protein-coupled receptors have been identified and are hypothesized to be responsible for roughly 80% of [https://en.wikipedia.org/wiki/Signal_transduction signal transduction].<ref name="Millar">PMID:20019124</ref> GPCRs are involved in a vast array of physiological processes within the body that range from interactions with [https://en.wikipedia.org/wiki/Dopamine dopamine] to effects on secretion of bile in the intestines.<ref name="Gui">PMID:11208724</ref> <ref name="Binder">PMID:1173461</ref> Due to the vast array of functions that these proteins serve and their high abundance within the body, these proteins have become major drug targets.<ref name="Fang">PMID:23573662</ref>

A critical topic in the understanding of GPCRs is the transition from the inactive to active state. This transition is responsible for the [https://en.wikipedia.org/wiki/Signal_transduction transduction] of a signal from the extracellular to the intracellular space. The transition occurs when a ligand, NTS in the case of NTSR1, binds to the receptor causing a [https://en.wikipedia.org/wiki/Conformational_change conformational change] in the protein that leads to the activation of the intracellular G protein. Currently no crystal structures of the receptor in its unbound, inactive form exist making the transition more difficult to study. NTSR1 can be seen in blue and the ligand NTS can be seen in green.<ref name="White">PMID:23051748</ref>
== Neurotensin ==
[https://en.wikipedia.org/wiki/Neurotensin Neurotensin (NTS)] is a 13-amino acid peptide originally isolated from [https://en.wikipedia.org/w/index.php?title=Bovinae&redirect=no bovine] [https://en.wikipedia.org/wiki/Hypothalamus hypothalamus]. NTS fulfills the roles of both a [https://en.wikipedia.org/wiki/Neurotransmitter neurotransmitter] and a [https://en.wikipedia.org/wiki/Neuromodulation neuromodulator] in the nervous system and a [https://en.wikipedia.org/wiki/Hormone hormone] in the periphery nervous system. NTS is a neuromodulator of dopamine transmission and of anterior [https://en.wikipedia.org/wiki/Pituitary_gland pituitary] hormone secretion. In the periphery of the digestive tract and cardiovascular system, NTS is a [https://en.wikipedia.org/w/index.php?title=Paracrine_signalling&redirect=no paracrine] and [https://en.wikipedia.org/wiki/Endocrine_system endocrine] modulator. Finally, NTS serves as a [https://en.wikipedia.org/wiki/Growth_factor growth factor] for many normal and cancerous cell types. <ref name="Vincent">PMID:10390649</ref>

Only the C-terminal tail of NTS, amino acids 8-13, were resolved in the <scene name='72/721539/Nts8_13/2'>crystal structure</scene>.(PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]The peptide is colored by element: carbon, oxygen, nitrogen.
== Structure ==
=== Overall Structure ===
[[Image:Nuerotensin membrane.jpg |100 px|left|thumb|Figure 1: Neurotensin Incorporation in Membrane ]]
Like other G protein-coupled receptors, the neurotensin receptor is composed of 3 distinct regions. An extracellular binding site where neurotensin binds and causes a conformational change of the protein. A region containing <scene name='72/727765/Overall_structure/4'>7 transmembrane alpha helices</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] that transduce the signal from the extracellular side of the cell membrane to the intracellular side. Each helix is colored differently for easy identification. Lastly, an intracellular region that when activated by a conformational change in the protein activates a [https://en.wikipedia.org/wiki/G_protein G protein] associated with this receptor. Currently no crystal structures of the inactive form of the neurotensin receptor available. Without a representation of the inactive form, the conformational changes caused by agonist binding are still not completely known.
=== Neurotensin Binding Site ===
Binding of NTS to the binding site is enriched by <scene name='72/721539/Binding_pocket_surface/4'>charge complementarity</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]between the positive NTS arginine side chains and the [https://en.wikipedia.org/wiki/Electronegativity electronegative] pocket. In addition, the C-terminus forms a <scene name='72/721539/Binding_site_charges/4'>salt bridge</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] with R328. Only three out of eight [https://en.wikipedia.org/wiki/Hydrogen_bond hydrogen bonds] are made between the side chains of NTS and the receptor. Most of the interactions are [https://en.wikipedia.org/wiki/Van_der_Waals_force van der Waals] interactions. The binding pocket is partially capped by a <scene name='72/721539/B-hairpin_loop/1'>Β-hairpin loop</scene> at the proximal end of the receptor protein's N-terminus.<ref name="White"/>
=== Hydrophobic Stacking ===
A major player in the transduction of the extracellular signal to the intracellular G protein is the <scene name='72/727765/Hydrogen_bonding_network/4'>hydrogen bonding network</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]that links the bound hormone with the [https://en.wikipedia.org/wiki/Hydrophobe hydrophobic] core of the neurotensin receptor. The carboxylate of L13 forms a hydrogen bond network with R327, R328, and Y324. The Y324, in turn, is brought into an orientation to make the formation of a <scene name='72/727765/Hydrophobic_stacking_4xee/2'>hydrophobic stacking</scene> (PDB Code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE]) network between F358, W321, A157, and F317 possible.<ref name="Krumm">PMID:23051748</ref> The conformational changes caused by this stacking allows for the signal to be moved from the extracellular binding site through the transmembrane helices of the receptor to the intracellular region activating the G protein.
== Sodium Binding Pocket ==
Conserved across all class A GPCRs, a <scene name='72/727765/Gw5_na_pocket_final/4'>sodium ion-binding pocket</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] is seen in the middle of TM2 helix. The ion is coordinated with a highly conserved D2.50 and four other contacts with oxygen atoms. Some of these oxygen atoms are sourced from water molecules. In order for G-protein activation, a <scene name='72/721539/4xee_na_binding_pocket/2'>hydrogen bond coordination</scene> (PDB Code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE]) with T3.39, S7.46 ,N7.49 of the NPxxY [https://en.wikipedia.org/wiki/Structural_motif motif], prevents the coordination of a Na+. <ref name="Krumm"/><ref name="Katritch">PMID:24767681</ref>
=== Allosteric Effects ===
Sodium ions are a negative [https://en.wikipedia.org/wiki/Allosteric_regulation allosteric] inhibitor to the binding of the neurotensin [https://en.wikipedia.org/wiki/Agonist agonist] to the binding site on the neurotensin receptor. D113 of the highly conserved D/RY motif and N365 of the highly conserved NPxxY motif form a substantial hydrogen bonding network with T156 and S362.<ref name="Krumm"/> This hydrogen bonding network prevents the incorporation of the sodium ion by collapsing upon itself and therefor filling the sodium binding pocket. W321 also works to inhibit the incorporation of the sodium ion by capping off the sodium binding pocket to not allow sodium to enter from the top. W321 uses van der Walls interactions with other amino acids in the binding pocket to place it in the conformation necessary to complete this task.
==Clinical Relevance==
NTSR1 is commonly expressed in various invasive [https://en.wikipedia.org/wiki/Cancer cancer] cell lines. It is prevalent in the [https://en.wikipedia.org/wiki/Colorectal_cancer colon cancer] [https://en.wikipedia.org/wiki/Adenocarcinoma adenocarcinoma], but is not found in adult colon cell types. NTSR1 is also found in aggressive [https://en.wikipedia.org/wiki/Prostate_cancer prostate cancer] cells, but not [https://en.wikipedia.org/wiki/Epithelium epithelial] prostate cells. In prostate cancer cells, binding of the NTS results in [https://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase mitogen-activated protein kinase (PKB)], [https://en.wikipedia.org/wiki/Phosphoinositide_3-kinase phosphoinositide-3 kinase (PI-3K)], [https://en.wikipedia.org/wiki/Epidermal_growth_factor_receptor epidermal growth factor receptor (EGFR)], [https://en.wikipedia.org/wiki/Proto-oncogene_tyrosine-protein_kinase_Src SRC], and [https://en.wikipedia.org/wiki/STAT5 STAT5] phosphorylation. These all result in increased DNA sythesis, [https://en.wikipedia.org/wiki/Cell_growth cell proliferation], and survival. Inhibition of NTSR1 and its downstream signaling represents a target for [https://en.wikipedia.org/wiki/Radiation_therapy radiotherapy]. [[Image: Meclinerant.jpg |100 px|left|thumb|Meclinerant]]NTSR1 can be inhibited by agonist [https://en.wikipedia.org/wiki/Meclinertant meclinertant] which has shown evidence for the inhibition of proliferation and prosurvival of cancer cells. Treatment of radiation and meclinerant has shown to provide selective treatment of cancer cells over normal cells, indicating the need for clinical trials of this approach. <ref name="Valerie">PMID:21903767</ref> <ref name="Kisfalvi">PMID:19679549</ref>

</StructureSection>
== References ==
<references/>

Sandbox reserved 1169

2016-04-17T22:04:37Z

Andrew Koelper:

==Neurotensin Receptor (NTSR1)==
<StructureSection | PDB=4GRV2 | Size =500 | Side=right | scene ='72/727765/Overall_structure/2' | caption='Neurotensin G-Protein Coupled Receptor (PDB Codes [http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV] and [http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE])'>__NoTOC__
== Introduction ==
The neurotensin receptor (NTSR1) belongs to the superfamily of proteins known as [http://proteopedia.org/wiki/index.php/G_protein-coupled_receptor G protein-coupled receptors] (GPCRs) and responds to the 13 amino acid hormone [https://en.wikipedia.org/wiki/Neurotensin neurotensin (NTS)]. Currently around 800 G protein-coupled receptors have been identified and are hypothesized to be responsible for roughly 80% of [https://en.wikipedia.org/wiki/Signal_transduction signal transduction].<ref name="Millar">PMID:20019124</ref> GPCRs are involved in a vast array of physiological processes within the body that range from interactions with [https://en.wikipedia.org/wiki/Dopamine dopamine] to effects on secretion of bile in the intestines.<ref name="Gui">PMID:11208724</ref> <ref name="Binder">PMID:1173461</ref> Due to the vast array of functions that these proteins serve and their high abundance within the body, these proteins have become major drug targets.<ref name="Fang">PMID:23573662</ref>

A critical topic in the understanding of GPCRs is the transition from the inactive to active state. This transition is responsible for the [https://en.wikipedia.org/wiki/Signal_transduction transduction] of a signal from the extracellular to the intracellular space. The transition occurs when a ligand, NTS in the case of NTSR1, binds to the receptor causing a [https://en.wikipedia.org/wiki/Conformational_change conformational change] in the protein that leads to the activation of the intracellular G protein. Currently no crystal structures of the receptor in its unbound, inactive form exist making the transition more difficult to study. NTSR1 can be seen in blue and the ligand NTS can be seen in green.<ref name="White">PMID:23051748</ref>
== Neurotensin ==
[https://en.wikipedia.org/wiki/Neurotensin Neurotensin (NTS)] is a 13-amino acid peptide originally isolated from [https://en.wikipedia.org/w/index.php?title=Bovinae&redirect=no bovine] [https://en.wikipedia.org/wiki/Hypothalamus hypothalamus]. NTS fulfills the roles of both a [https://en.wikipedia.org/wiki/Neurotransmitter neurotransmitter] and a [https://en.wikipedia.org/wiki/Neuromodulation neuromodulator] in the nervous system and a [https://en.wikipedia.org/wiki/Hormone hormone] in the periphery nervous system. NTS is a neuromodulator of dopamine transmission and of anterior [https://en.wikipedia.org/wiki/Pituitary_gland pituitary] hormone secretion. In the periphery of the digestive tract and cardiovascular system, NTS is a [https://en.wikipedia.org/w/index.php?title=Paracrine_signalling&redirect=no paracrine] and [https://en.wikipedia.org/wiki/Endocrine_system endocrine] modulator. Finally, NTS serves as a [https://en.wikipedia.org/wiki/Growth_factor growth factor] for many normal and cancerous cell types. <ref name="Vincent">PMID:10390649</ref>

Only the C-terminal tail of NTS, amino acids 8-13, were resolved in the <scene name='72/721539/Nts8_13/2'>crystal structure</scene>.(PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]The peptide is colored by element: carbon, oxygen, nitrogen.
== Structure ==
=== Overall Structure ===
[[Image:Nuerotensin membrane.jpg |100 px|left|thumb|Figure 1: Neurotensin Incorporation in Membrane ]]
Like other G protein-coupled receptors, the neurotensin receptor is composed of 3 distinct regions. An extracellular binding site where neurotensin binds and causes a conformational change of the protein. A region containing <scene name='72/727765/Overall_structure/4'>7 transmembrane alpha helices</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] that transduce the signal from the extracellular side of the cell membrane to the intracellular side. Lastly, an intracellular region that when activated by a conformational change in the protein activates a [https://en.wikipedia.org/wiki/G_protein G protein] associated with this receptor. Currently no crystal structures of the inactive form of the neurotensin receptor available. Without a representation of the inactive form, the conformational changes caused by agonist binding are still not completely known.
=== Neurotensin Binding Site ===
Binding of NTS to the binding site is enriched by <scene name='72/721539/Binding_pocket_surface/4'>charge complementarity</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]between the positive NTS arginine side chains and the [https://en.wikipedia.org/wiki/Electronegativity electronegative] pocket. In addition, the C-terminus forms a <scene name='72/721539/Binding_site_charges/4'>salt bridge</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] with R328. Only three out of eight [https://en.wikipedia.org/wiki/Hydrogen_bond hydrogen bonds] are made between the side chains of NTS and the receptor. Most of the interactions are [https://en.wikipedia.org/wiki/Van_der_Waals_force van der Waals] interactions. The binding pocket is partially capped by a <scene name='72/721539/B-hairpin_loop/1'>Β-hairpin loop</scene> at the proximal end of the receptor protein's N-terminus.<ref name="White"/>
=== Hydrophobic Stacking ===
A major player in the transduction of the extracellular signal to the intracellular G protein is the <scene name='72/727765/Hydrogen_bonding_network/4'>hydrogen bonding network</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]that links the bound hormone with the [https://en.wikipedia.org/wiki/Hydrophobe hydrophobic] core of the neurotensin receptor. The carboxylate of L13 forms a hydrogen bond network with R327, R328, and Y324. The Y324, in turn, is brought into an orientation to make the formation of a <scene name='72/727765/Hydrophobic_stacking_4xee/2'>hydrophobic stacking</scene> (PDB Code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE]) network between F358, W321, A157, and F317 possible.<ref name="Krumm">PMID:23051748</ref> The conformational changes caused by this stacking allows for the signal to be moved from the extracellular binding site through the transmembrane helices of the receptor to the intracellular region activating the G protein.
== Sodium Binding Pocket ==
Conserved across all class A GPCRs, a <scene name='72/727765/Gw5_na_pocket_final/4'>sodium ion-binding pocket</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] is seen in the middle of TM2 helix. The ion is coordinated with a highly conserved D2.50 and four other contacts with oxygen atoms. Some of these oxygen atoms are sourced from water molecules. In order for G-protein activation, a <scene name='72/721539/4xee_na_binding_pocket/2'>hydrogen bond coordination</scene> (PDB Code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE]) with T3.39, S7.46 ,N7.49 of the NPxxY [https://en.wikipedia.org/wiki/Structural_motif motif], prevents the coordination of a Na+. <ref name="Krumm"/><ref name="Katritch">PMID:24767681</ref>
=== Allosteric Effects ===
Sodium ions are a negative [https://en.wikipedia.org/wiki/Allosteric_regulation allosteric] inhibitor to the binding of the neurotensin [https://en.wikipedia.org/wiki/Agonist agonist] to the binding site on the neurotensin receptor. D113 of the highly conserved D/RY motif and N365 of the highly conserved NPxxY motif form a substantial hydrogen bonding network with T156 and S362.<ref name="Krumm"/> This hydrogen bonding network prevents the incorporation of the sodium ion by collapsing upon itself and therefor filling the sodium binding pocket. W321 also works to inhibit the incorporation of the sodium ion by capping off the sodium binding pocket to not allow sodium to enter from the top. W321 uses van der Walls interactions with other amino acids in the binding pocket to place it in the conformation necessary to complete this task.
==Clinical Relevance==
NTSR1 is commonly expressed in various invasive [https://en.wikipedia.org/wiki/Cancer cancer] cell lines. It is prevalent in the [https://en.wikipedia.org/wiki/Colorectal_cancer colon cancer] [https://en.wikipedia.org/wiki/Adenocarcinoma adenocarcinoma], but is not found in adult colon cell types. NTSR1 is also found in aggressive [https://en.wikipedia.org/wiki/Prostate_cancer prostate cancer] cells, but not [https://en.wikipedia.org/wiki/Epithelium epithelial] prostate cells. In prostate cancer cells, binding of the NTS results in [https://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase mitogen-activated protein kinase (PKB)], [https://en.wikipedia.org/wiki/Phosphoinositide_3-kinase phosphoinositide-3 kinase (PI-3K)], [https://en.wikipedia.org/wiki/Epidermal_growth_factor_receptor epidermal growth factor receptor (EGFR)], [https://en.wikipedia.org/wiki/Proto-oncogene_tyrosine-protein_kinase_Src SRC], and [https://en.wikipedia.org/wiki/STAT5 STAT5] phosphorylation. These all result in increased DNA sythesis, [https://en.wikipedia.org/wiki/Cell_growth cell proliferation], and survival. Inhibition of NTSR1 and its downstream signaling represents a target for [https://en.wikipedia.org/wiki/Radiation_therapy radiotherapy]. [[Image: Meclinerant.jpg |100 px|left|thumb|Meclinerant]]NTSR1 can be inhibited by agonist [https://en.wikipedia.org/wiki/Meclinertant meclinertant] which has shown evidence for the inhibition of proliferation and prosurvival of cancer cells. Treatment of radiation and meclinerant has shown to provide selective treatment of cancer cells over normal cells, indicating the need for clinical trials of this approach. <ref name="Valerie">PMID:21903767</ref> <ref name="Kisfalvi">PMID:19679549</ref>

</StructureSection>
== References ==
<references/>

Sandbox reserved 1169

2016-04-17T22:01:19Z

Andrew Koelper:

==Neurotensin Receptor (NTSR1)==
<StructureSection | PDB=4GRV2 | Size =500 | Side=right | scene ='72/727765/Overall_structure/2' | caption='Neurotensin G-Protein Coupled Receptor (PDB Codes [http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV] and [http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE])'>__NoTOC__
== Introduction ==
The neurotensin receptor (NTSR1) belongs to the superfamily of proteins known as [http://proteopedia.org/wiki/index.php/G_protein-coupled_receptor G protein-coupled receptors] (GPCRs) and responds to the 13 amino acid hormone [https://en.wikipedia.org/wiki/Neurotensin neurotensin (NTS)]. Currently around 800 G protein-coupled receptors have been identified and are hypothesized to be responsible for roughly 80% of [https://en.wikipedia.org/wiki/Signal_transduction signal transduction].<ref name="Millar">PMID:20019124</ref> GPCRs are involved in a vast array of physiological processes within the body that range from interactions with [https://en.wikipedia.org/wiki/Dopamine dopamine] to effects on secretion of bile in the intestines.<ref name="Gui">PMID:11208724</ref> <ref name="Binder">PMID:1173461</ref> Due to the vast array of functions that these proteins serve and their high abundance within the body, these proteins have become major drug targets.<ref name="Fang">PMID:23573662</ref>

A critical topic in the understanding of GPCRs is the transition from the inactive to active state. This transition is responsible for the [https://en.wikipedia.org/wiki/Signal_transduction transduction] of a signal from the extracellular to the intracellular space. The transition occurs when a ligand, NTS in the case of NTSR1, binds to the receptor causing a [https://en.wikipedia.org/wiki/Conformational_change conformational change] in the protein that leads to the activation of the intracellular G protein. Currently no crystal structures of the receptor in its unbound, inactive form exist making the transition more difficult to study. NTSR1 can be seen in blue and the ligand NTS can be seen in green.<ref name="White">PMID:23051748</ref>
== Neurotensin ==
[https://en.wikipedia.org/wiki/Neurotensin Neurotensin (NTS)] is a 13-amino acid peptide originally isolated from [https://en.wikipedia.org/w/index.php?title=Bovinae&redirect=no bovine] [https://en.wikipedia.org/wiki/Hypothalamus hypothalamus]. NTS fulfills the roles of both a [https://en.wikipedia.org/wiki/Neurotransmitter neurotransmitter] and a [https://en.wikipedia.org/wiki/Neuromodulation neuromodulator] in the nervous system and a [https://en.wikipedia.org/wiki/Hormone hormone] in the periphery nervous system. NTS is a neuromodulator of dopamine transmission and of anterior [https://en.wikipedia.org/wiki/Pituitary_gland pituitary] hormone secretion. In the periphery of the digestive tract and cardiovascular system, NTS is a [https://en.wikipedia.org/w/index.php?title=Paracrine_signalling&redirect=no paracrine] and [https://en.wikipedia.org/wiki/Endocrine_system endocrine] modulator. Finally, NTS serves as a [https://en.wikipedia.org/wiki/Growth_factor growth factor] for many normal and cancerous cell types.<ref name="Vincent">PMID:10390649</ref>

Only the C-terminal tail of NTS, amino acids 8-13, were resolved in the <scene name='72/721539/Nts8_13/2'>crystal structure</scene>.(PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]
== Structure ==
=== Overall Structure ===
[[Image:Nuerotensin membrane.jpg |100 px|left|thumb|Figure 1: Neurotensin Incorporation in Membrane ]]
Like other G protein-coupled receptors, the neurotensin receptor is composed of 3 distinct regions. An extracellular binding site where neurotensin binds and causes a conformational change of the protein. A region containing <scene name='72/727765/Overall_structure/4'>7 transmembrane alpha helices</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] that transduce the signal from the extracellular side of the cell membrane to the intracellular side. Lastly, an intracellular region that when activated by a conformational change in the protein activates a [https://en.wikipedia.org/wiki/G_protein G protein] associated with this receptor. Currently no crystal structures of the inactive form of the neurotensin receptor available. Without a representation of the inactive form, the conformational changes caused by agonist binding are still not completely known.
=== Neurotensin Binding Site ===
Binding of NTS to the binding site is enriched by <scene name='72/721539/Binding_pocket_surface/4'>charge complementarity</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]between the positive NTS arginine side chains and the [https://en.wikipedia.org/wiki/Electronegativity electronegative] pocket. In addition, the C-terminus forms a <scene name='72/721539/Binding_site_charges/4'>salt bridge</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] with R328. Only three out of eight [https://en.wikipedia.org/wiki/Hydrogen_bond hydrogen bonds] are made between the side chains of NTS and the receptor. Most of the interactions are [https://en.wikipedia.org/wiki/Van_der_Waals_force van der Waals] interactions. The binding pocket is partially capped by a <scene name='72/721539/B-hairpin_loop/1'>Β-hairpin loop</scene> at the proximal end of the receptor protein's N-terminus.<ref name="White"/>
=== Hydrophobic Stacking ===
A major player in the transduction of the extracellular signal to the intracellular G protein is the <scene name='72/727765/Hydrogen_bonding_network/4'>hydrogen bonding network</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]that links the bound hormone with the [https://en.wikipedia.org/wiki/Hydrophobe hydrophobic] core of the neurotensin receptor. The carboxylate of L13 forms a hydrogen bond network with R327, R328, and Y324. The Y324, in turn, is brought into an orientation to make the formation of a <scene name='72/727765/Hydrophobic_stacking_4xee/2'>hydrophobic stacking</scene> (PDB Code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE]) network between F358, W321, A157, and F317 possible.<ref name="Krumm">PMID:23051748</ref> The conformational changes caused by this stacking allows for the signal to be moved from the extracellular binding site through the transmembrane helices of the receptor to the intracellular region activating the G protein.
== Sodium Binding Pocket ==
Conserved across all class A GPCRs, a <scene name='72/727765/Gw5_na_pocket_final/4'>sodium ion-binding pocket</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] is seen in the middle of TM2 helix. The ion is coordinated with a highly conserved D2.50 and four other contacts with oxygen atoms. Some of these oxygen atoms are sourced from water molecules. In order for G-protein activation, a <scene name='72/721539/4xee_na_binding_pocket/2'>hydrogen bond coordination</scene> (PDB Code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE]) with T3.39, S7.46 ,N7.49 of the NPxxY [https://en.wikipedia.org/wiki/Structural_motif motif], prevents the coordination of a Na+. <ref name="Krumm"/><ref name="Katritch">PMID:24767681</ref>
=== Allosteric Effects ===
Sodium ions are a negative [https://en.wikipedia.org/wiki/Allosteric_regulation allosteric] inhibitor to the binding of the neurotensin [https://en.wikipedia.org/wiki/Agonist agonist] to the binding site on the neurotensin receptor. D113 of the highly conserved D/RY motif and N365 of the highly conserved NPxxY motif form a substantial hydrogen bonding network with T156 and S362.<ref name="Krumm"/> This hydrogen bonding network prevents the incorporation of the sodium ion by collapsing upon itself and therefor filling the sodium binding pocket. W321 also works to inhibit the incorporation of the sodium ion by capping off the sodium binding pocket to not allow sodium to enter from the top. W321 uses van der Walls interactions with other amino acids in the binding pocket to place it in the conformation necessary to complete this task.
==Clinical Relevance==
NTSR1 is commonly expressed in various invasive [https://en.wikipedia.org/wiki/Cancer cancer] cell lines. It is prevalent in the [https://en.wikipedia.org/wiki/Colorectal_cancer colon cancer] [https://en.wikipedia.org/wiki/Adenocarcinoma adenocarcinoma], but is not found in adult colon cell types. NTSR1 is also found in aggressive [https://en.wikipedia.org/wiki/Prostate_cancer prostate cancer] cells, but not [https://en.wikipedia.org/wiki/Epithelium epithelial] prostate cells. In prostate cancer cells, binding of the NTS results in [https://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase mitogen-activated protein kinase (PKB)], [https://en.wikipedia.org/wiki/Phosphoinositide_3-kinase phosphoinositide-3 kinase (PI-3K)], [https://en.wikipedia.org/wiki/Epidermal_growth_factor_receptor epidermal growth factor receptor (EGFR)], [https://en.wikipedia.org/wiki/Proto-oncogene_tyrosine-protein_kinase_Src SRC], and [https://en.wikipedia.org/wiki/STAT5 STAT5] phosphorylation. These all result in increased DNA sythesis, [https://en.wikipedia.org/wiki/Cell_growth cell proliferation], and survival. Inhibition of NTSR1 and its downstream signaling represents a target for [https://en.wikipedia.org/wiki/Radiation_therapy radiotherapy]. [[Image: Meclinerant.jpg |100 px|left|thumb|Meclinerant]]NTSR1 can be inhibited by agonist [https://en.wikipedia.org/wiki/Meclinertant meclinertant] which has shown evidence for the inhibition of proliferation and prosurvival of cancer cells. Treatment of radiation and meclinerant has shown to provide selective treatment of cancer cells over normal cells, indicating the need for clinical trials of this approach. <ref name="Valerie">PMID:21903767</ref> <ref name="Kisfalvi">PMID:19679549</ref>

</StructureSection>
== References ==
<references/>

Sandbox reserved 1169

2016-04-17T19:12:28Z

Andrew Koelper:

==Neurotensin Receptor (NTSR1)==
<StructureSection | PDB=4GRV2 | Size =500 | Side=right | scene ='72/727765/Overall_structure/2' | caption='Neurotensin G-Protein Coupled Receptor (PDB Codes [http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV] and [http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE])'>__NoTOC__
== Introduction ==
The neurotensin receptor (NTSR1) belongs to the superfamily of proteins known as [http://proteopedia.org/wiki/index.php/G_protein-coupled_receptor G protein-coupled receptors] (GPCRs) and responds to the 13 amino acid hormone [https://en.wikipedia.org/wiki/Neurotensin neurotensin (NTS)]. Currently around 800 G protein-coupled receptors have been identified and are hypothesized to be responsible for roughly 80% of [https://en.wikipedia.org/wiki/Signal_transduction signal transduction].<ref name="Millar">PMID:20019124</ref> GPCRs are involved in a vast array of physiological processes within the body that range from interactions with [https://en.wikipedia.org/wiki/Dopamine dopamine] to effects on secretion of bile in the intestines.<ref name="Gui">PMID:11208724</ref> <ref name="Binder">PMID:1173461</ref> Due to the vast array of functions that these proteins serve and their high abundance within the body, these proteins have become major drug targets.<ref name="Fang">PMID:23573662</ref>

A critical topic in the understanding of GPCRs is the transition from the inactive to active state. This transition is responsible for the [https://en.wikipedia.org/wiki/Signal_transduction transduction] of a signal from the extracellular to the intracellular space. The transition occurs when a ligand, NTS in the case of NTSR1, binds to the receptor causing a [https://en.wikipedia.org/wiki/Conformational_change conformational change] in the protein that leads to the activation of the intracellular G protein. Currently no crystal structures of the receptor in its unbound, inactive form exist making the transition more difficult to study. <ref name="White">PMID:23051748</ref>
== Neurotensin ==
[https://en.wikipedia.org/wiki/Neurotensin Neurotensin (NTS)] is a 13-amino acid peptide originally isolated from [https://en.wikipedia.org/w/index.php?title=Bovinae&redirect=no bovine] [https://en.wikipedia.org/wiki/Hypothalamus hypothalamus]. NTS fulfills the roles of both a [https://en.wikipedia.org/wiki/Neurotransmitter neurotransmitter] and a [https://en.wikipedia.org/wiki/Neuromodulation neuromodulator] in the nervous system and a [https://en.wikipedia.org/wiki/Hormone hormone] in the periphery nervous system. NTS is a neuromodulator of dopamine transmission and of anterior [https://en.wikipedia.org/wiki/Pituitary_gland pituitary] hormone secretion. In the periphery of the digestive tract and cardiovascular system, NTS is a [https://en.wikipedia.org/w/index.php?title=Paracrine_signalling&redirect=no paracrine] and [https://en.wikipedia.org/wiki/Endocrine_system endocrine] modulator. Finally, NTS serves as a [https://en.wikipedia.org/wiki/Growth_factor growth factor] for many normal and cancerous cell types.<ref name="Vincent">PMID:10390649</ref>

Only the C-terminal tail of NTS, amino acids 8-13, were resolved in the <scene name='72/721539/Nts8_13/2'>crystal structure</scene>.(PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]
== Structure ==
=== Overall Structure ===
[[Image:Nuerotensin membrane.jpg |100 px|left|thumb|Figure 1: Neurotensin Incorporation in Membrane ]]
Like other G protein-coupled receptors, the neurotensin receptor is composed of 3 distinct regions. An extracellular binding site where neurotensin binds and causes a conformational change of the protein. A region containing <scene name='72/727765/Overall_structure/4'>7 transmembrane alpha helices</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] that transduce the signal from the extracellular side of the cell membrane to the intracellular side. Lastly, an intracellular region that when activated by a conformational change in the protein activates a [https://en.wikipedia.org/wiki/G_protein G protein] associated with this receptor. Currently no crystal structures of the inactive form of the neurotensin receptor available. Without a representation of the inactive form, the conformational changes caused by agonist binding are still not completely known.
=== Neurotensin Binding Site ===
Binding of NTS to the binding site is enriched by <scene name='72/721539/Binding_pocket_surface/4'>charge complementarity</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]between the positive NTS arginine side chains and the [https://en.wikipedia.org/wiki/Electronegativity electronegative] pocket. In addition, the C-terminus forms a <scene name='72/721539/Binding_site_charges/4'>salt bridge</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] with R328. Only three out of eight [https://en.wikipedia.org/wiki/Hydrogen_bond hydrogen bonds] are made between the side chains of NTS and the receptor. Most of the interactions are [https://en.wikipedia.org/wiki/Van_der_Waals_force van der Waals] interactions. The binding pocket is partially capped by a <scene name='72/721539/B-hairpin_loop/1'>Β-hairpin loop</scene> at the proximal end of the receptor protein's N-terminus.<ref name="White"/>
=== Hydrophobic Stacking ===
A major player in the transduction of the extracellular signal to the intracellular G protein is the <scene name='72/727765/Hydrogen_bonding_network/4'>hydrogen bonding network</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]that links the bound hormone with the [https://en.wikipedia.org/wiki/Hydrophobe hydrophobic] core of the neurotensin receptor. The carboxylate of L13 forms a hydrogen bond network with R327, R328, and Y324. The Y324, in turn, is brought into an orientation to make the formation of a <scene name='72/727765/Hydrophobic_stacking_4xee/2'>hydrophobic stacking</scene> (PDB Code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE]) network between F358, W321, A157, and F317 possible.<ref name="Krumm">PMID:23051748</ref> The conformational changes caused by this stacking allows for the signal to be moved from the extracellular binding site through the transmembrane helices of the receptor to the intracellular region activating the G protein.
== Sodium Binding Pocket ==
Conserved across all class A GPCRs, a <scene name='72/727765/Gw5_na_pocket_final/4'>sodium ion-binding pocket</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] is seen in the middle of TM2 helix. The ion is coordinated with a highly conserved D2.50 and four other contacts with oxygen atoms. Some of these oxygen atoms are sourced from water molecules. In order for G-protein activation, a <scene name='72/721539/4xee_na_binding_pocket/2'>hydrogen bond coordination</scene> (PDB Code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE]) with T3.39, S7.46 ,N7.49 of the NPxxY [https://en.wikipedia.org/wiki/Structural_motif motif], prevents the coordination of a Na+. <ref name="Krumm"/><ref name="Katritch">PMID:24767681</ref>
=== Allosteric Effects ===
Sodium ions are a negative [https://en.wikipedia.org/wiki/Allosteric_regulation allosteric] inhibitor to the binding of the neurotensin [https://en.wikipedia.org/wiki/Agonist agonist] to the binding site on the neurotensin receptor. D113 of the highly conserved D/RY motif and N365 of the highly conserved NPxxY motif form a substantial hydrogen bonding network with T156 and S362.<ref name="Krumm"/> This hydrogen bonding network prevents the incorporation of the sodium ion by collapsing upon itself and therefor filling the sodium binding pocket. W321 also works to inhibit the incorporation of the sodium ion by capping off the sodium binding pocket to not allow sodium to enter from the top. W321 uses van der Walls interactions with other amino acids in the binding pocket to place it in the conformation necessary to complete this task.
==Clinical Relevance==
NTSR1 is commonly expressed in various invasive [https://en.wikipedia.org/wiki/Cancer cancer] cell lines. It is prevalent in the [https://en.wikipedia.org/wiki/Colorectal_cancer colon cancer] [https://en.wikipedia.org/wiki/Adenocarcinoma adenocarcinoma], but is not found in adult colon cell types. NTSR1 is also found in aggressive [https://en.wikipedia.org/wiki/Prostate_cancer prostate cancer] cells, but not [https://en.wikipedia.org/wiki/Epithelium epithelial] prostate cells. In prostate cancer cells, binding of the NTS results in [https://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase mitogen-activated protein kinase (PKB)], [https://en.wikipedia.org/wiki/Phosphoinositide_3-kinase phosphoinositide-3 kinase (PI-3K)], [https://en.wikipedia.org/wiki/Epidermal_growth_factor_receptor epidermal growth factor receptor (EGFR)], [https://en.wikipedia.org/wiki/Proto-oncogene_tyrosine-protein_kinase_Src SRC], and [https://en.wikipedia.org/wiki/STAT5 STAT5] phosphorylation. These all result in increased DNA sythesis, [https://en.wikipedia.org/wiki/Cell_growth cell proliferation], and survival. Inhibition of NTSR1 and its downstream signaling represents a target for [https://en.wikipedia.org/wiki/Radiation_therapy radiotherapy]. [[Image: Meclinerant.jpg |100 px|left|thumb|Meclinerant]]NTSR1 can be inhibited by agonist [https://en.wikipedia.org/wiki/Meclinertant meclinertant] which has shown evidence for the inhibition of proliferation and prosurvival of cancer cells. Treatment of radiation and meclinerant has shown to provide selective treatment of cancer cells over normal cells, indicating the need for clinical trials of this approach. <ref name="Valerie">PMID:21903767</ref> <ref name="Kisfalvi">PMID:19679549</ref>

</StructureSection>
== References ==
<references/>

Sandbox reserved 1169

2016-04-17T19:08:00Z

Andrew Koelper:

==Neurotensin Receptor (NTSR1)==
<StructureSection | PDB=4GRV2 | Size =500 | Side=right | scene ='72/727765/Overall_structure/2' | caption='Neurotensin G-Protein Coupled Receptor (PDB Codes [http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV] and [http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE])'>__NoTOC__
== Introduction ==
The neurotensin receptor (NTSR1) belongs to the superfamily of proteins known as [http://proteopedia.org/wiki/index.php/G_protein-coupled_receptor G protein-coupled receptors] (GPCRs) and responds to the 13 amino acid hormone [https://en.wikipedia.org/wiki/Neurotensin neurotensin (NTS)]. Currently around 800 G protein-coupled receptors have been identified and are hypothesized to be responsible for roughly 80% of [https://en.wikipedia.org/wiki/Signal_transduction signal transduction].<ref name="Millar">PMID:20019124</ref> GPCRs are involved in a vast array of physiological processes within the body that range from interactions with [https://en.wikipedia.org/wiki/Dopamine dopamine] to effects on secretion of bile in the intestines.<ref name="Gui">PMID:11208724</ref> <ref name="Binder">PMID:1173461</ref> Due to the vast array of functions that these proteins serve and their high abundance within the body, these proteins have become major drug targets.<ref name="Fang">PMID:23573662</ref>

A critical topic in the understanding of GPCRs is the transition from the inactive to active state. This transition is responsible for the [https://en.wikipedia.org/wiki/Signal_transduction transduction] of a signal from the extracellular to the intracellular space. The transition occurs when a ligand, NTS in the case of NTSR1, binds to the receptor causing a [https://en.wikipedia.org/wiki/Conformational_change conformational change] in the protein that leads to the activation of the intracellular G protein. Currently no crystal structures of the receptor in its unbound, inactive form exist making the transition more difficult to study. <ref name="White">PMID:23051748</ref>
== Neurotensin ==
[https://en.wikipedia.org/wiki/Neurotensin Neurotensin (NTS)] is a 13-amino acid peptide originally isolated from [https://en.wikipedia.org/w/index.php?title=Bovinae&redirect=no bovine] [https://en.wikipedia.org/wiki/Hypothalamus hypothalamus]. NTS fulfills the roles of both a [https://en.wikipedia.org/wiki/Neurotransmitter neurotransmitter] and a [https://en.wikipedia.org/wiki/Neuromodulation neuromodulator] in the nervous system and a [https://en.wikipedia.org/wiki/Hormone hormone] in the periphery nervous system. NTS is a neuromodulator of dopamine transmission and of anterior [https://en.wikipedia.org/wiki/Pituitary_gland pituitary] hormone secretion. In the periphery of the digestive tract and cardiovascular system, NTS is a [https://en.wikipedia.org/w/index.php?title=Paracrine_signalling&redirect=no paracrine] and [https://en.wikipedia.org/wiki/Endocrine_system endocrine] modulator. Finally, NTS serves as a [https://en.wikipedia.org/wiki/Growth_factor growth factor] for many normal and cancerous cell types.<ref name="Vincent">PMID:10390649</ref>

Only the C-terminal tail of NTS, amino acids 8-13, were resolved in the <scene name='72/721539/Nts8_13/2'>crystal structure</scene>.(PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]
== Structure ==
=== Overall Structure ===
[[Image:Nuerotensin membrane.jpg |100 px|left|thumb|Figure 1: Neurotensin Incorporation in Membrane ]]
Like other G protein-coupled receptors, the neurotensin receptor is composed of 3 distinct regions. An extracellular binding site where neurotensin binds and causes a conformational change of the protein. A region containing <scene name='72/727765/Overall_structure/4'>7 transmembrane alpha helices</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] that transduce the signal from the extracellular side of the cell membrane to the intracellular side. Lastly, an intracellular region that when activated by a conformational change in the protein activates a [https://en.wikipedia.org/wiki/G_protein G protein] associated with this receptor. Currently no crystal structures of the inactive form of the neurotensin receptor available. Without a representation of the inactive form, the conformational changes caused by agonist binding are still not completely known.
=== Neurotensin Binding Site ===
Binding of NTS to the binding site is enriched by <scene name='72/721539/Binding_pocket_surface/4'>charge complementarity</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]between the positive NTS arginine side chains and the [https://en.wikipedia.org/wiki/Electronegativity electronegative] pocket. In addition, the C-terminus forms a <scene name='72/721539/Binding_site_charges/4'>salt bridge</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] with R328. Only three out of eight [https://en.wikipedia.org/wiki/Hydrogen_bond hydrogen bonds] are made between the side chains of NTS and the receptor. Most of the interactions are [https://en.wikipedia.org/wiki/Van_der_Waals_force van der Waals] interactions. The binding pocket is partially capped by a <scene name='72/721539/B-hairpin_loop/1'>Β-hairpin loop</scene> at the proximal end of the receptor protein's N-terminus.<ref name="White"/>
=== Hydrophobic Stacking ===
A major player in the transduction of the extracellular signal to the intracellular G protein is the <scene name='72/727765/Hydrogen_bonding_network/3'>hydrogen bonding network</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]that links the bound hormone with the [https://en.wikipedia.org/wiki/Hydrophobe hydrophobic] core of the neurotensin receptor. The carboxylate of L13 forms a hydrogen bond network with R327, R328, and Y324. The Y324, in turn, is brought into an orientation to make the formation of a <scene name='72/727765/Hydrophobic_stacking_4xee/2'>hydrophobic stacking</scene> (PDB Code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE]) network between F358, W321, A157, and F317 possible.<ref name="Krumm">PMID:23051748</ref> The conformational changes caused by this stacking allows for the signal to be moved from the extracellular binding site through the transmembrane helices of the receptor to the intracellular region activating the G protein.
== Sodium Binding Pocket ==
Conserved across all class A GPCRs, a <scene name='72/727765/Gw5_na_pocket_final/4'>sodium ion-binding pocket</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] is seen in the middle of TM2 helix. The ion is coordinated with a highly conserved D2.50 and four other contacts with oxygen atoms. Some of these oxygen atoms are sourced from water molecules. In order for G-protein activation, a <scene name='72/721539/4xee_na_binding_pocket/2'>hydrogen bond coordination</scene> (PDB Code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE]) with T3.39, S7.46 ,N7.49 of the NPxxY [https://en.wikipedia.org/wiki/Structural_motif motif], prevents the coordination of a Na+. <ref name="Krumm"/><ref name="Katritch">PMID:24767681</ref>
=== Allosteric Effects ===
Sodium ions are a negative [https://en.wikipedia.org/wiki/Allosteric_regulation allosteric] inhibitor to the binding of the neurotensin [https://en.wikipedia.org/wiki/Agonist agonist] to the binding site on the neurotensin receptor. D113 of the highly conserved D/RY motif and N365 of the highly conserved NPxxY motif form a substantial hydrogen bonding network with T156 and S362.<ref name="Krumm"/> This hydrogen bonding network prevents the incorporation of the sodium ion by collapsing upon itself and therefor filling the sodium binding pocket. W321 also works to inhibit the incorporation of the sodium ion by capping off the sodium binding pocket to not allow sodium to enter from the top. W321 uses van der Walls interactions with other amino acids in the binding pocket to place it in the conformation necessary to complete this task.
==Clinical Relevance==
NTSR1 is commonly expressed in various invasive [https://en.wikipedia.org/wiki/Cancer cancer] cell lines. It is prevalent in the [https://en.wikipedia.org/wiki/Colorectal_cancer colon cancer] [https://en.wikipedia.org/wiki/Adenocarcinoma adenocarcinoma], but is not found in adult colon cell types. NTSR1 is also found in aggressive [https://en.wikipedia.org/wiki/Prostate_cancer prostate cancer] cells, but not [https://en.wikipedia.org/wiki/Epithelium epithelial] prostate cells. In prostate cancer cells, binding of the NTS results in [https://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase mitogen-activated protein kinase (PKB)], [https://en.wikipedia.org/wiki/Phosphoinositide_3-kinase phosphoinositide-3 kinase (PI-3K)], [https://en.wikipedia.org/wiki/Epidermal_growth_factor_receptor epidermal growth factor receptor (EGFR)], [https://en.wikipedia.org/wiki/Proto-oncogene_tyrosine-protein_kinase_Src SRC], and [https://en.wikipedia.org/wiki/STAT5 STAT5] phosphorylation. These all result in increased DNA sythesis, [https://en.wikipedia.org/wiki/Cell_growth cell proliferation], and survival. Inhibition of NTSR1 and its downstream signaling represents a target for [https://en.wikipedia.org/wiki/Radiation_therapy radiotherapy]. [[Image: Meclinerant.jpg |100 px|left|thumb|Meclinerant]]NTSR1 can be inhibited by agonist [https://en.wikipedia.org/wiki/Meclinertant meclinertant] which has shown evidence for the inhibition of proliferation and prosurvival of cancer cells. Treatment of radiation and meclinerant has shown to provide selective treatment of cancer cells over normal cells, indicating the need for clinical trials of this approach. <ref name="Valerie">PMID:21903767</ref> <ref name="Kisfalvi">PMID:19679549</ref>

</StructureSection>
== References ==
<references/>

Sandbox reserved 1169

2016-04-17T19:02:32Z

Andrew Koelper:

==Neurotensin Receptor (NTSR1)==
<StructureSection | PDB=4GRV2 | Size =500 | Side=right | scene ='72/727765/Overall_structure/2' | caption='Neurotensin G-Protein Coupled Receptor (PDB Codes [http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV] and [http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE])'>__NoTOC__
== Introduction ==
The neurotensin receptor (NTSR1) belongs to the superfamily of proteins known as [http://proteopedia.org/wiki/index.php/G_protein-coupled_receptor G protein-coupled receptors] (GPCRs) and responds to the 13 amino acid hormone [https://en.wikipedia.org/wiki/Neurotensin neurotensin (NTS)]. Currently around 800 G protein-coupled receptors have been identified and are hypothesized to be responsible for roughly 80% of [https://en.wikipedia.org/wiki/Signal_transduction signal transduction].<ref name="Millar">PMID:20019124</ref> GPCRs are involved in a vast array of physiological processes within the body that range from interactions with [https://en.wikipedia.org/wiki/Dopamine dopamine] to effects on secretion of bile in the intestines.<ref name="Gui">PMID:11208724</ref> <ref name="Binder">PMID:1173461</ref> Due to the vast array of functions that these proteins serve and their high abundance within the body, these proteins have become major drug targets.<ref name="Fang">PMID:23573662</ref>

A critical topic in the understanding of GPCRs is the transition from the inactive to active state. This transition is responsible for the [https://en.wikipedia.org/wiki/Signal_transduction transduction] of a signal from the extracellular to the intracellular space. The transition occurs when a ligand, NTS in the case of NTSR1, binds to the receptor causing a [https://en.wikipedia.org/wiki/Conformational_change conformational change] in the protein that leads to the activation of the intracellular G protein. Currently no crystal structures of the receptor in its unbound, inactive form exist making the transition more difficult to study. <ref name="White">PMID:23051748</ref>
== Neurotensin ==
[https://en.wikipedia.org/wiki/Neurotensin Neurotensin (NTS)] is a 13-amino acid peptide originally isolated from [https://en.wikipedia.org/w/index.php?title=Bovinae&redirect=no bovine] [https://en.wikipedia.org/wiki/Hypothalamus hypothalamus]. NTS fulfills the roles of both a [https://en.wikipedia.org/wiki/Neurotransmitter neurotransmitter] and a [https://en.wikipedia.org/wiki/Neuromodulation neuromodulator] in the nervous system and a [https://en.wikipedia.org/wiki/Hormone hormone] in the periphery nervous system. NTS is a neuromodulator of dopamine transmission and of anterior [https://en.wikipedia.org/wiki/Pituitary_gland pituitary] hormone secretion. In the periphery of the digestive tract and cardiovascular system, NTS is a [https://en.wikipedia.org/w/index.php?title=Paracrine_signalling&redirect=no paracrine] and [https://en.wikipedia.org/wiki/Endocrine_system endocrine] modulator. Finally, NTS serves as a [https://en.wikipedia.org/wiki/Growth_factor growth factor] for many normal and cancerous cell types.<ref name="Vincent">PMID:10390649</ref>

Only the C-terminal tail of NTS, amino acids 8-13, were resolved in the <scene name='72/721539/Nts8_13/2'>crystal structure</scene>.(PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]
== Structure ==
=== Overall Structure ===
[[Image:Nuerotensin membrane.jpg |100 px|left|thumb|Figure 1: Neurotensin Incorporation in Membrane ]]
Like other G protein-coupled receptors, the neurotensin receptor is composed of 3 distinct regions. An extracellular binding site where neurotensin binds and causes a conformational change of the protein. A region containing <scene name='72/727765/Overall_structure/4'>7 transmembrane alpha helices</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] that transduce the signal from the extracellular side of the cell membrane to the intracellular side. Lastly, an intracellular region that when activated by a conformational change in the protein activates a [https://en.wikipedia.org/wiki/G_protein G protein] associated with this receptor. Currently no crystal structures of the inactive form of the neurotensin receptor available. Without a representation of the inactive form, the conformational changes caused by agonist binding are still not completely known.
=== Neurotensin Binding Site ===
Binding of NTS to the binding site is enriched by <scene name='72/721539/Binding_pocket_surface/4'>charge complementarity</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]between the positive NTS arginine side chains and the [https://en.wikipedia.org/wiki/Electronegativity electronegative] pocket. In addition, the C-terminus forms a <scene name='72/721539/Binding_site_charges/3'>salt bridge</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] with R328. Only three out of eight [https://en.wikipedia.org/wiki/Hydrogen_bond hydrogen bonds] are made between the side chains of NTS and the receptor. Most of the interactions are [https://en.wikipedia.org/wiki/Van_der_Waals_force van der Waals] interactions. The binding pocket is partially capped by a <scene name='72/721539/B-hairpin_loop/1'>Β-hairpin loop</scene> at the proximal end of the receptor protein's N-terminus.<ref name="White"/>
=== Hydrophobic Stacking ===
A major player in the transduction of the extracellular signal to the intracellular G protein is the <scene name='72/727765/Hydrogen_bonding_network/3'>hydrogen bonding network</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]that links the bound hormone with the [https://en.wikipedia.org/wiki/Hydrophobe hydrophobic] core of the neurotensin receptor. The carboxylate of L13 forms a hydrogen bond network with R327, R328, and Y324. The Y324, in turn, is brought into an orientation to make the formation of a <scene name='72/727765/Hydrophobic_stacking_4xee/2'>hydrophobic stacking</scene> (PDB Code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE]) network between F358, W321, A157, and F317 possible.<ref name="Krumm">PMID:23051748</ref> The conformational changes caused by this stacking allows for the signal to be moved from the extracellular binding site through the transmembrane helices of the receptor to the intracellular region activating the G protein.
== Sodium Binding Pocket ==
Conserved across all class A GPCRs, a <scene name='72/727765/Gw5_na_pocket_final/4'>sodium ion-binding pocket</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] is seen in the middle of TM2 helix. The ion is coordinated with a highly conserved D2.50 and four other contacts with oxygen atoms. Some of these oxygen atoms are sourced from water molecules. In order for G-protein activation, a <scene name='72/721539/4xee_na_binding_pocket/2'>hydrogen bond coordination</scene> (PDB Code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE]) with T3.39, S7.46 ,N7.49 of the NPxxY [https://en.wikipedia.org/wiki/Structural_motif motif], prevents the coordination of a Na+. <ref name="Krumm"/><ref name="Katritch">PMID:24767681</ref>
=== Allosteric Effects ===
Sodium ions are a negative [https://en.wikipedia.org/wiki/Allosteric_regulation allosteric] inhibitor to the binding of the neurotensin [https://en.wikipedia.org/wiki/Agonist agonist] to the binding site on the neurotensin receptor. D113 of the highly conserved D/RY motif and N365 of the highly conserved NPxxY motif form a substantial hydrogen bonding network with T156 and S362.<ref name="Krumm"/> This hydrogen bonding network prevents the incorporation of the sodium ion by collapsing upon itself and therefor filling the sodium binding pocket. W321 also works to inhibit the incorporation of the sodium ion by capping off the sodium binding pocket to not allow sodium to enter from the top. W321 uses van der Walls interactions with other amino acids in the binding pocket to place it in the conformation necessary to complete this task.
==Clinical Relevance==
NTSR1 is commonly expressed in various invasive [https://en.wikipedia.org/wiki/Cancer cancer] cell lines. It is prevalent in the [https://en.wikipedia.org/wiki/Colorectal_cancer colon cancer] [https://en.wikipedia.org/wiki/Adenocarcinoma adenocarcinoma], but is not found in adult colon cell types. NTSR1 is also found in aggressive [https://en.wikipedia.org/wiki/Prostate_cancer prostate cancer] cells, but not [https://en.wikipedia.org/wiki/Epithelium epithelial] prostate cells. In prostate cancer cells, binding of the NTS results in [https://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase mitogen-activated protein kinase (PKB)], [https://en.wikipedia.org/wiki/Phosphoinositide_3-kinase phosphoinositide-3 kinase (PI-3K)], [https://en.wikipedia.org/wiki/Epidermal_growth_factor_receptor epidermal growth factor receptor (EGFR)], [https://en.wikipedia.org/wiki/Proto-oncogene_tyrosine-protein_kinase_Src SRC], and [https://en.wikipedia.org/wiki/STAT5 STAT5] phosphorylation. These all result in increased DNA sythesis, [https://en.wikipedia.org/wiki/Cell_growth cell proliferation], and survival. Inhibition of NTSR1 and its downstream signaling represents a target for [https://en.wikipedia.org/wiki/Radiation_therapy radiotherapy]. [[Image: Meclinerant.jpg |100 px|left|thumb|Meclinerant]]NTSR1 can be inhibited by agonist [https://en.wikipedia.org/wiki/Meclinertant meclinertant] which has shown evidence for the inhibition of proliferation and prosurvival of cancer cells. Treatment of radiation and meclinerant has shown to provide selective treatment of cancer cells over normal cells, indicating the need for clinical trials of this approach. <ref name="Valerie">PMID:21903767</ref> <ref name="Kisfalvi">PMID:19679549</ref>

</StructureSection>
== References ==
<references/>

Sandbox reserved 1169

2016-04-17T18:57:41Z

Andrew Koelper:

==Neurotensin Receptor (NTSR1)==
<StructureSection | PDB=4GRV2 | Size =500 | Side=right | scene ='72/727765/Overall_structure/2' | caption='Neurotensin G-Protein Coupled Receptor (PDB Codes [http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV] and [http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE])'>__NoTOC__
== Introduction ==
The neurotensin receptor (NTSR1) belongs to the superfamily of proteins known as [http://proteopedia.org/wiki/index.php/G_protein-coupled_receptor G protein-coupled receptors] (GPCRs) and responds to the 13 amino acid hormone [https://en.wikipedia.org/wiki/Neurotensin neurotensin (NTS)]. Currently around 800 G protein-coupled receptors have been identified and are hypothesized to be responsible for roughly 80% of [https://en.wikipedia.org/wiki/Signal_transduction signal transduction].<ref name="Millar">PMID:20019124</ref> GPCRs are involved in a vast array of physiological processes within the body that range from interactions with [https://en.wikipedia.org/wiki/Dopamine dopamine] to effects on secretion of bile in the intestines.<ref name="Gui">PMID:11208724</ref> <ref name="Binder">PMID:1173461</ref> Due to the vast array of functions that these proteins serve and their high abundance within the body, these proteins have become major drug targets.<ref name="Fang">PMID:23573662</ref>

A critical topic in the understanding of GPCRs is the transition from the inactive to active state. This transition is responsible for the [https://en.wikipedia.org/wiki/Signal_transduction transduction] of a signal from the extracellular to the intracellular space. The transition occurs when a ligand, NTS in the case of NTSR1, binds to the receptor causing a [https://en.wikipedia.org/wiki/Conformational_change conformational change] in the protein that leads to the activation of the intracellular G protein. Currently no crystal structures of the receptor in its unbound, inactive form exist making the transition more difficult to study. <ref name="White">PMID:23051748</ref>
== Neurotensin ==
[https://en.wikipedia.org/wiki/Neurotensin Neurotensin (NTS)] is a 13-amino acid peptide originally isolated from [https://en.wikipedia.org/w/index.php?title=Bovinae&redirect=no bovine] [https://en.wikipedia.org/wiki/Hypothalamus hypothalamus]. NTS fulfills the roles of both a [https://en.wikipedia.org/wiki/Neurotransmitter neurotransmitter] and a [https://en.wikipedia.org/wiki/Neuromodulation neuromodulator] in the nervous system and a [https://en.wikipedia.org/wiki/Hormone hormone] in the periphery nervous system. NTS is a neuromodulator of dopamine transmission and of anterior [https://en.wikipedia.org/wiki/Pituitary_gland pituitary] hormone secretion. In the periphery of the digestive tract and cardiovascular system, NTS is a [https://en.wikipedia.org/w/index.php?title=Paracrine_signalling&redirect=no paracrine] and [https://en.wikipedia.org/wiki/Endocrine_system endocrine] modulator. Finally, NTS serves as a [https://en.wikipedia.org/wiki/Growth_factor growth factor] for many normal and cancerous cell types.<ref name="Vincent">PMID:10390649</ref>

Only the C-terminal tail of NTS, amino acids 8-13, were resolved in the <scene name='72/721539/Nts8_13/2'>crystal structure</scene>.(PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]
== Structure ==
=== Overall Structure ===
[[Image:Nuerotensin membrane.jpg |100 px|left|thumb|Figure 1: Neurotensin Incorporation in Membrane ]]
Like other G protein-coupled receptors, the neurotensin receptor is composed of 3 distinct regions. An extracellular binding site where neurotensin binds and causes a conformational change of the protein. A region containing <scene name='72/727765/Overall_structure/4'>7 transmembrane alpha helices</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] that transduce the signal from the extracellular side of the cell membrane to the intracellular side. Lastly, an intracellular region that when activated by a conformational change in the protein activates a [https://en.wikipedia.org/wiki/G_protein G protein] associated with this receptor. Currently no crystal structures of the inactive form of the neurotensin receptor available. Without a representation of the inactive form, the conformational changes caused by agonist binding are still not completely known.
=== Neurotensin Binding Site ===
Binding of NTS to the binding site is enriched by <scene name='72/721539/Binding_pocket_surface/3'>charge complementarity</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]between the positive NTS arginine side chains and the [https://en.wikipedia.org/wiki/Electronegativity electronegative] pocket. In addition, the C-terminus forms a <scene name='72/721539/Binding_site_charges/2'>salt bridge</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] with R328. Only three out of eight [https://en.wikipedia.org/wiki/Hydrogen_bond hydrogen bonds] are made between the side chains of NTS and the receptor. Most of the interactions are [https://en.wikipedia.org/wiki/Van_der_Waals_force van der Waals] interactions. The binding pocket is partially capped by a [https://en.wikipedia.org/wiki/Beta_hairpin β-hairpin loop] at the proximal end of the receptor protein's N-terminus.<ref name="White"/>
=== Hydrophobic Stacking ===
A major player in the transduction of the extracellular signal to the intracellular G protein is the <scene name='72/727765/Hydrogen_bonding_network/1'>hydrogen bonding network</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]that links the bound hormone with the [https://en.wikipedia.org/wiki/Hydrophobe hydrophobic] core of the neurotensin receptor. The carboxylate of L13 forms a hydrogen bond network with R327, R328, and Y324. The Y324, in turn, is brought into an orientation to make the formation of a <scene name='72/727765/Hydrophobic_stacking_4xee/1'>hydrophobic stacking</scene> (PDB Code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE]) network between F358, W321, A157, and F317 possible.<ref name="Krumm">PMID:23051748</ref> The conformational changes caused by this stacking allows for the signal to be moved from the extracellular binding site through the transmembrane helices of the receptor to the intracellular region activating the G protein.
== Sodium Binding Pocket ==
Conserved across all class A GPCRs, a <scene name='72/727765/Gw5_na_pocket_final/2'>sodium ion-binding pocket</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] is seen in the middle of TM2 helix. The ion is coordinated with a highly conserved D2.50 and four other contacts with oxygen atoms. Some of these oxygen atoms are sourced from water molecules. In order for G-protein activation, a <scene name='72/721539/4xee_na_binding_pocket/1'>hydrogen bond network</scene> (PDB Code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE]) with T3.39, S7.46 ,N7.49 of the NPxxY [https://en.wikipedia.org/wiki/Structural_motif motif], prevents the coordination of a Na+. <ref name="Krumm"/><ref name="Katritch">PMID:24767681</ref>
=== Allosteric Effects ===
Sodium ions are a negative [https://en.wikipedia.org/wiki/Allosteric_regulation allosteric] inhibitor to the binding of the neurotensin [https://en.wikipedia.org/wiki/Agonist agonist] to the binding site on the neurotensin receptor. D113 of the highly conserved D/RY motif and N365 of the highly conserved NPxxY motif form a substantial hydrogen bonding network with T156 and S362.<ref name="Krumm"/> This hydrogen bonding network prevents the incorporation of the sodium ion by collapsing upon itself and therefor filling the sodium binding pocket. W321 also works to inhibit the incorporation of the sodium ion by capping off the sodium binding pocket to not allow sodium to enter from the top. W321 uses van der Walls interactions with other amino acids in the binding pocket to place it in the conformation necessary to complete this task.
==Clinical Relevance==
NTSR1 is commonly expressed in various invasive [https://en.wikipedia.org/wiki/Cancer cancer] cell lines. It is prevalent in the [https://en.wikipedia.org/wiki/Colorectal_cancer colon cancer] [https://en.wikipedia.org/wiki/Adenocarcinoma adenocarcinoma], but is not found in adult colon cell types. NTSR1 is also found in aggressive [https://en.wikipedia.org/wiki/Prostate_cancer prostate cancer] cells, but not [https://en.wikipedia.org/wiki/Epithelium epithelial] prostate cells. In prostate cancer cells, binding of the NTS results in [https://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase mitogen-activated protein kinase (PKB)], [https://en.wikipedia.org/wiki/Phosphoinositide_3-kinase phosphoinositide-3 kinase (PI-3K)], [https://en.wikipedia.org/wiki/Epidermal_growth_factor_receptor epidermal growth factor receptor (EGFR)], [https://en.wikipedia.org/wiki/Proto-oncogene_tyrosine-protein_kinase_Src SRC], and [https://en.wikipedia.org/wiki/STAT5 STAT5] phosphorylation. These all result in increased DNA sythesis, [https://en.wikipedia.org/wiki/Cell_growth cell proliferation], and survival. Inhibition of NTSR1 and its downstream signaling represents a target for [https://en.wikipedia.org/wiki/Radiation_therapy radiotherapy]. [[Image: Meclinerant.jpg |100 px|left|thumb|Meclinerant]]NTSR1 can be inhibited by agonist [https://en.wikipedia.org/wiki/Meclinertant meclinertant] which has shown evidence for the inhibition of proliferation and prosurvival of cancer cells. Treatment of radiation and meclinerant has shown to provide selective treatment of cancer cells over normal cells, indicating the need for clinical trials of this approach. <ref name="Valerie">PMID:21903767</ref> <ref name="Kisfalvi">PMID:19679549</ref>

</StructureSection>
== References ==
<references/>

Sandbox reserved 1169

2016-04-17T18:57:06Z

Andrew Koelper:

==Neurotensin Receptor (NTSR1)==
<StructureSection load='4GRV2.pdb' size='500' frame= 'true' align='right' caption='Neurotensin G-Protein Coupled Receptor (PDB Codes [http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV] and [http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE])' scene='72/727765/Overall_structure/2'/>__NoTOC__

<StructureSection | PDB=4GRV2 | Size =500 | Side=right | scene ='72/727765/Overall_structure/2' | caption='Neurotensin G-Protein Coupled Receptor (PDB Codes [http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV] and [http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE])'>__NoTOC__
== Introduction ==
The neurotensin receptor (NTSR1) belongs to the superfamily of proteins known as [http://proteopedia.org/wiki/index.php/G_protein-coupled_receptor G protein-coupled receptors] (GPCRs) and responds to the 13 amino acid hormone [https://en.wikipedia.org/wiki/Neurotensin neurotensin (NTS)]. Currently around 800 G protein-coupled receptors have been identified and are hypothesized to be responsible for roughly 80% of [https://en.wikipedia.org/wiki/Signal_transduction signal transduction].<ref name="Millar">PMID:20019124</ref> GPCRs are involved in a vast array of physiological processes within the body that range from interactions with [https://en.wikipedia.org/wiki/Dopamine dopamine] to effects on secretion of bile in the intestines.<ref name="Gui">PMID:11208724</ref> <ref name="Binder">PMID:1173461</ref> Due to the vast array of functions that these proteins serve and their high abundance within the body, these proteins have become major drug targets.<ref name="Fang">PMID:23573662</ref>

A critical topic in the understanding of GPCRs is the transition from the inactive to active state. This transition is responsible for the [https://en.wikipedia.org/wiki/Signal_transduction transduction] of a signal from the extracellular to the intracellular space. The transition occurs when a ligand, NTS in the case of NTSR1, binds to the receptor causing a [https://en.wikipedia.org/wiki/Conformational_change conformational change] in the protein that leads to the activation of the intracellular G protein. Currently no crystal structures of the receptor in its unbound, inactive form exist making the transition more difficult to study. <ref name="White">PMID:23051748</ref>
== Neurotensin ==
[https://en.wikipedia.org/wiki/Neurotensin Neurotensin (NTS)] is a 13-amino acid peptide originally isolated from [https://en.wikipedia.org/w/index.php?title=Bovinae&redirect=no bovine] [https://en.wikipedia.org/wiki/Hypothalamus hypothalamus]. NTS fulfills the roles of both a [https://en.wikipedia.org/wiki/Neurotransmitter neurotransmitter] and a [https://en.wikipedia.org/wiki/Neuromodulation neuromodulator] in the nervous system and a [https://en.wikipedia.org/wiki/Hormone hormone] in the periphery nervous system. NTS is a neuromodulator of dopamine transmission and of anterior [https://en.wikipedia.org/wiki/Pituitary_gland pituitary] hormone secretion. In the periphery of the digestive tract and cardiovascular system, NTS is a [https://en.wikipedia.org/w/index.php?title=Paracrine_signalling&redirect=no paracrine] and [https://en.wikipedia.org/wiki/Endocrine_system endocrine] modulator. Finally, NTS serves as a [https://en.wikipedia.org/wiki/Growth_factor growth factor] for many normal and cancerous cell types.<ref name="Vincent">PMID:10390649</ref>

Only the C-terminal tail of NTS, amino acids 8-13, were resolved in the <scene name='72/721539/Nts8_13/2'>crystal structure</scene>.(PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]
== Structure ==
=== Overall Structure ===
[[Image:Nuerotensin membrane.jpg |100 px|left|thumb|Figure 1: Neurotensin Incorporation in Membrane ]]
Like other G protein-coupled receptors, the neurotensin receptor is composed of 3 distinct regions. An extracellular binding site where neurotensin binds and causes a conformational change of the protein. A region containing <scene name='72/727765/Overall_structure/4'>7 transmembrane alpha helices</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] that transduce the signal from the extracellular side of the cell membrane to the intracellular side. Lastly, an intracellular region that when activated by a conformational change in the protein activates a [https://en.wikipedia.org/wiki/G_protein G protein] associated with this receptor. Currently no crystal structures of the inactive form of the neurotensin receptor available. Without a representation of the inactive form, the conformational changes caused by agonist binding are still not completely known.
=== Neurotensin Binding Site ===
Binding of NTS to the binding site is enriched by <scene name='72/721539/Binding_pocket_surface/3'>charge complementarity</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]between the positive NTS arginine side chains and the [https://en.wikipedia.org/wiki/Electronegativity electronegative] pocket. In addition, the C-terminus forms a <scene name='72/721539/Binding_site_charges/2'>salt bridge</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] with R328. Only three out of eight [https://en.wikipedia.org/wiki/Hydrogen_bond hydrogen bonds] are made between the side chains of NTS and the receptor. Most of the interactions are [https://en.wikipedia.org/wiki/Van_der_Waals_force van der Waals] interactions. The binding pocket is partially capped by a [https://en.wikipedia.org/wiki/Beta_hairpin β-hairpin loop] at the proximal end of the receptor protein's N-terminus.<ref name="White"/>
=== Hydrophobic Stacking ===
A major player in the transduction of the extracellular signal to the intracellular G protein is the <scene name='72/727765/Hydrogen_bonding_network/1'>hydrogen bonding network</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]that links the bound hormone with the [https://en.wikipedia.org/wiki/Hydrophobe hydrophobic] core of the neurotensin receptor. The carboxylate of L13 forms a hydrogen bond network with R327, R328, and Y324. The Y324, in turn, is brought into an orientation to make the formation of a <scene name='72/727765/Hydrophobic_stacking_4xee/1'>hydrophobic stacking</scene> (PDB Code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE]) network between F358, W321, A157, and F317 possible.<ref name="Krumm">PMID:23051748</ref> The conformational changes caused by this stacking allows for the signal to be moved from the extracellular binding site through the transmembrane helices of the receptor to the intracellular region activating the G protein.
== Sodium Binding Pocket ==
Conserved across all class A GPCRs, a <scene name='72/727765/Gw5_na_pocket_final/2'>sodium ion-binding pocket</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] is seen in the middle of TM2 helix. The ion is coordinated with a highly conserved D2.50 and four other contacts with oxygen atoms. Some of these oxygen atoms are sourced from water molecules. In order for G-protein activation, a <scene name='72/721539/4xee_na_binding_pocket/1'>hydrogen bond network</scene> (PDB Code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE]) with T3.39, S7.46 ,N7.49 of the NPxxY [https://en.wikipedia.org/wiki/Structural_motif motif], prevents the coordination of a Na+. <ref name="Krumm"/><ref name="Katritch">PMID:24767681</ref>
=== Allosteric Effects ===
Sodium ions are a negative [https://en.wikipedia.org/wiki/Allosteric_regulation allosteric] inhibitor to the binding of the neurotensin [https://en.wikipedia.org/wiki/Agonist agonist] to the binding site on the neurotensin receptor. D113 of the highly conserved D/RY motif and N365 of the highly conserved NPxxY motif form a substantial hydrogen bonding network with T156 and S362.<ref name="Krumm"/> This hydrogen bonding network prevents the incorporation of the sodium ion by collapsing upon itself and therefor filling the sodium binding pocket. W321 also works to inhibit the incorporation of the sodium ion by capping off the sodium binding pocket to not allow sodium to enter from the top. W321 uses van der Walls interactions with other amino acids in the binding pocket to place it in the conformation necessary to complete this task.
==Clinical Relevance==
NTSR1 is commonly expressed in various invasive [https://en.wikipedia.org/wiki/Cancer cancer] cell lines. It is prevalent in the [https://en.wikipedia.org/wiki/Colorectal_cancer colon cancer] [https://en.wikipedia.org/wiki/Adenocarcinoma adenocarcinoma], but is not found in adult colon cell types. NTSR1 is also found in aggressive [https://en.wikipedia.org/wiki/Prostate_cancer prostate cancer] cells, but not [https://en.wikipedia.org/wiki/Epithelium epithelial] prostate cells. In prostate cancer cells, binding of the NTS results in [https://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase mitogen-activated protein kinase (PKB)], [https://en.wikipedia.org/wiki/Phosphoinositide_3-kinase phosphoinositide-3 kinase (PI-3K)], [https://en.wikipedia.org/wiki/Epidermal_growth_factor_receptor epidermal growth factor receptor (EGFR)], [https://en.wikipedia.org/wiki/Proto-oncogene_tyrosine-protein_kinase_Src SRC], and [https://en.wikipedia.org/wiki/STAT5 STAT5] phosphorylation. These all result in increased DNA sythesis, [https://en.wikipedia.org/wiki/Cell_growth cell proliferation], and survival. Inhibition of NTSR1 and its downstream signaling represents a target for [https://en.wikipedia.org/wiki/Radiation_therapy radiotherapy]. [[Image: Meclinerant.jpg |100 px|left|thumb|Meclinerant]]NTSR1 can be inhibited by agonist [https://en.wikipedia.org/wiki/Meclinertant meclinertant] which has shown evidence for the inhibition of proliferation and prosurvival of cancer cells. Treatment of radiation and meclinerant has shown to provide selective treatment of cancer cells over normal cells, indicating the need for clinical trials of this approach. <ref name="Valerie">PMID:21903767</ref> <ref name="Kisfalvi">PMID:19679549</ref>

</StructureSection>
== References ==
<references/>

Sandbox reserved 1169

2016-04-17T18:40:47Z

Andrew Koelper:

==Neurotensin Receptor (NTSR1)==
<StructureSection load='4GRV2.pdb' size='500' frame= 'true' align='right' caption='Neurotensin G-Protein Coupled Receptor (PDB Codes [http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV] and [http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE])' scene='72/727765/Overall_structure/2'/>__NoTOC__
== Introduction ==
The neurotensin receptor (NTSR1) belongs to the superfamily of proteins known as [http://proteopedia.org/wiki/index.php/G_protein-coupled_receptor G protein-coupled receptors] (GPCRs) and responds to the 13 amino acid hormone [https://en.wikipedia.org/wiki/Neurotensin neurotensin (NTS)]. Currently around 800 G protein-coupled receptors have been identified and are hypothesized to be responsible for roughly 80% of [https://en.wikipedia.org/wiki/Signal_transduction signal transduction].<ref name="Millar">PMID:20019124</ref> GPCRs are involved in a vast array of physiological processes within the body that range from interactions with [https://en.wikipedia.org/wiki/Dopamine dopamine] to effects on secretion of bile in the intestines.<ref name="Gui">PMID:11208724</ref> <ref name="Binder">PMID:1173461</ref> Due to the vast array of functions that these proteins serve and their high abundance within the body, these proteins have become major drug targets.<ref name="Fang">PMID:23573662</ref>

A critical topic in the understanding of GPCRs is the transition from the inactive to active state. This transition is responsible for the [https://en.wikipedia.org/wiki/Signal_transduction transduction] of a signal from the extracellular to the intracellular space. The transition occurs when a ligand, NTS in the case of NTSR1, binds to the receptor causing a [https://en.wikipedia.org/wiki/Conformational_change conformational change] in the protein that leads to the activation of the intracellular G protein. Currently no crystal structures of the receptor in its unbound, inactive form exist making the transition more difficult to study. <ref name="White">PMID:23051748</ref>
== Neurotensin ==
[https://en.wikipedia.org/wiki/Neurotensin Neurotensin (NTS)] is a 13-amino acid peptide originally isolated from [https://en.wikipedia.org/w/index.php?title=Bovinae&redirect=no bovine] [https://en.wikipedia.org/wiki/Hypothalamus hypothalamus]. NTS fulfills the roles of both a [https://en.wikipedia.org/wiki/Neurotransmitter neurotransmitter] and a [https://en.wikipedia.org/wiki/Neuromodulation neuromodulator] in the nervous system and a [https://en.wikipedia.org/wiki/Hormone hormone] in the periphery nervous system. NTS is a neuromodulator of dopamine transmission and of anterior [https://en.wikipedia.org/wiki/Pituitary_gland pituitary] hormone secretion. In the periphery of the digestive tract and cardiovascular system, NTS is a [https://en.wikipedia.org/w/index.php?title=Paracrine_signalling&redirect=no paracrine] and [https://en.wikipedia.org/wiki/Endocrine_system endocrine] modulator. Finally, NTS serves as a [https://en.wikipedia.org/wiki/Growth_factor growth factor] for many normal and cancerous cell types.<ref name="Vincent">PMID:10390649</ref>

Only the C-terminal tail of NTS, amino acids 8-13, were resolved in the <scene name='72/721539/Nts8_13/2'>crystal structure</scene>.(PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]
== Structure ==
=== Overall Structure ===
[[Image:Nuerotensin membrane.jpg |100 px|left|thumb|Figure 1: Neurotensin Incorporation in Membrane ]]
Like other G protein-coupled receptors, the neurotensin receptor is composed of 3 distinct regions. An extracellular binding site where neurotensin binds and causes a conformational change of the protein. A region containing <scene name='72/727765/Overall_structure/4'>7 transmembrane alpha helices</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] that transduce the signal from the extracellular side of the cell membrane to the intracellular side. Lastly, an intracellular region that when activated by a conformational change in the protein activates a [https://en.wikipedia.org/wiki/G_protein G protein] associated with this receptor. Currently no crystal structures of the inactive form of the neurotensin receptor available. Without a representation of the inactive form, the conformational changes caused by agonist binding are still not completely known.
=== Neurotensin Binding Site ===
Binding of NTS to the binding site is enriched by <scene name='72/721539/Binding_pocket_surface/3'>charge complementarity</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]between the positive NTS arginine side chains and the [https://en.wikipedia.org/wiki/Electronegativity electronegative] pocket. In addition, the C-terminus forms a <scene name='72/721539/Binding_site_charges/2'>salt bridge</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] with R328. Only three out of eight [https://en.wikipedia.org/wiki/Hydrogen_bond hydrogen bonds] are made between the side chains of NTS and the receptor. Most of the interactions are [https://en.wikipedia.org/wiki/Van_der_Waals_force van der Waals] interactions. The binding pocket is partially capped by a [https://en.wikipedia.org/wiki/Beta_hairpin β-hairpin loop] at the proximal end of the receptor protein's N-terminus.<ref name="White"/>
=== Hydrophobic Stacking ===
A major player in the transduction of the extracellular signal to the intracellular G protein is the <scene name='72/727765/Hydrogen_bonding_network/1'>hydrogen bonding network</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]that links the bound hormone with the [https://en.wikipedia.org/wiki/Hydrophobe hydrophobic] core of the neurotensin receptor. The carboxylate of L13 forms a hydrogen bond network with R327, R328, and Y324. The Y324, in turn, is brought into an orientation to make the formation of a <scene name='72/727765/Hydrophobic_stacking_4xee/1'>hydrophobic stacking</scene> (PDB Code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE]) network between F358, W321, A157, and F317 possible.<ref name="Krumm">PMID:23051748</ref> The conformational changes caused by this stacking allows for the signal to be moved from the extracellular binding site through the transmembrane helices of the receptor to the intracellular region activating the G protein.
== Sodium Binding Pocket ==
Conserved across all class A GPCRs, a <scene name='72/727765/Gw5_na_pocket_final/2'>sodium ion-binding pocket</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] is seen in the middle of TM2 helix. The ion is coordinated with a highly conserved D2.50 and four other contacts with oxygen atoms. Some of these oxygen atoms are sourced from water molecules. In order for G-protein activation, a <scene name='72/721539/4xee_na_binding_pocket/1'>hydrogen bond network</scene> (PDB Code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE]) with T3.39, S7.46 ,N7.49 of the NPxxY [https://en.wikipedia.org/wiki/Structural_motif motif], prevents the coordination of a Na+. <ref name="Krumm"/><ref name="Katritch">PMID:24767681</ref>
=== Allosteric Effects ===
Sodium ions are a negative [https://en.wikipedia.org/wiki/Allosteric_regulation allosteric] inhibitor to the binding of the neurotensin [https://en.wikipedia.org/wiki/Agonist agonist] to the binding site on the neurotensin receptor. D113 of the highly conserved D/RY motif and N365 of the highly conserved NPxxY motif form a substantial hydrogen bonding network with T156 and S362.<ref name="Krumm"/> This hydrogen bonding network prevents the incorporation of the sodium ion by collapsing upon itself and therefor filling the sodium binding pocket. W321 also works to inhibit the incorporation of the sodium ion by capping off the sodium binding pocket to not allow sodium to enter from the top. W321 uses van der Walls interactions with other amino acids in the binding pocket to place it in the conformation necessary to complete this task.
==Clinical Relevance==
NTSR1 is commonly expressed in various invasive [https://en.wikipedia.org/wiki/Cancer cancer] cell lines. It is prevalent in the [https://en.wikipedia.org/wiki/Colorectal_cancer colon cancer] [https://en.wikipedia.org/wiki/Adenocarcinoma adenocarcinoma], but is not found in adult colon cell types. NTSR1 is also found in aggressive [https://en.wikipedia.org/wiki/Prostate_cancer prostate cancer] cells, but not [https://en.wikipedia.org/wiki/Epithelium epithelial] prostate cells. In prostate cancer cells, binding of the NTS results in [https://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase mitogen-activated protein kinase (PKB)], [https://en.wikipedia.org/wiki/Phosphoinositide_3-kinase phosphoinositide-3 kinase (PI-3K)], [https://en.wikipedia.org/wiki/Epidermal_growth_factor_receptor epidermal growth factor receptor (EGFR)], [https://en.wikipedia.org/wiki/Proto-oncogene_tyrosine-protein_kinase_Src SRC], and [https://en.wikipedia.org/wiki/STAT5 STAT5] phosphorylation. These all result in increased DNA sythesis, [https://en.wikipedia.org/wiki/Cell_growth cell proliferation], and survival. Inhibition of NTSR1 and its downstream signaling represents a target for [https://en.wikipedia.org/wiki/Radiation_therapy radiotherapy]. [[Image: Meclinerant.jpg |100 px|left|thumb|Meclinerant]]NTSR1 can be inhibited by agonist [https://en.wikipedia.org/wiki/Meclinertant meclinertant] which has shown evidence for the inhibition of proliferation and prosurvival of cancer cells. Treatment of radiation and meclinerant has shown to provide selective treatment of cancer cells over normal cells, indicating the need for clinical trials of this approach. <ref name="Valerie">PMID:21903767</ref> <ref name="Kisfalvi">PMID:19679549</ref>

</StructureSection>
== References ==
<references/>

Sandbox reserved 1169

2016-04-17T18:40:12Z

Andrew Koelper:

==Neurotensin Receptor (NTSR1)==
<StructureSection load='4GRV2.pdb' size='500' frame= 'true' side='right' caption='Neurotensin G-Protein Coupled Receptor (PDB Codes [http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV] and [http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE])' scene='72/727765/Overall_structure/2'/>__NoTOC__
== Introduction ==
The neurotensin receptor (NTSR1) belongs to the superfamily of proteins known as [http://proteopedia.org/wiki/index.php/G_protein-coupled_receptor G protein-coupled receptors] (GPCRs) and responds to the 13 amino acid hormone [https://en.wikipedia.org/wiki/Neurotensin neurotensin (NTS)]. Currently around 800 G protein-coupled receptors have been identified and are hypothesized to be responsible for roughly 80% of [https://en.wikipedia.org/wiki/Signal_transduction signal transduction].<ref name="Millar">PMID:20019124</ref> GPCRs are involved in a vast array of physiological processes within the body that range from interactions with [https://en.wikipedia.org/wiki/Dopamine dopamine] to effects on secretion of bile in the intestines.<ref name="Gui">PMID:11208724</ref> <ref name="Binder">PMID:1173461</ref> Due to the vast array of functions that these proteins serve and their high abundance within the body, these proteins have become major drug targets.<ref name="Fang">PMID:23573662</ref>

A critical topic in the understanding of GPCRs is the transition from the inactive to active state. This transition is responsible for the [https://en.wikipedia.org/wiki/Signal_transduction transduction] of a signal from the extracellular to the intracellular space. The transition occurs when a ligand, NTS in the case of NTSR1, binds to the receptor causing a [https://en.wikipedia.org/wiki/Conformational_change conformational change] in the protein that leads to the activation of the intracellular G protein. Currently no crystal structures of the receptor in its unbound, inactive form exist making the transition more difficult to study. <ref name="White">PMID:23051748</ref>
== Neurotensin ==
[https://en.wikipedia.org/wiki/Neurotensin Neurotensin (NTS)] is a 13-amino acid peptide originally isolated from [https://en.wikipedia.org/w/index.php?title=Bovinae&redirect=no bovine] [https://en.wikipedia.org/wiki/Hypothalamus hypothalamus]. NTS fulfills the roles of both a [https://en.wikipedia.org/wiki/Neurotransmitter neurotransmitter] and a [https://en.wikipedia.org/wiki/Neuromodulation neuromodulator] in the nervous system and a [https://en.wikipedia.org/wiki/Hormone hormone] in the periphery nervous system. NTS is a neuromodulator of dopamine transmission and of anterior [https://en.wikipedia.org/wiki/Pituitary_gland pituitary] hormone secretion. In the periphery of the digestive tract and cardiovascular system, NTS is a [https://en.wikipedia.org/w/index.php?title=Paracrine_signalling&redirect=no paracrine] and [https://en.wikipedia.org/wiki/Endocrine_system endocrine] modulator. Finally, NTS serves as a [https://en.wikipedia.org/wiki/Growth_factor growth factor] for many normal and cancerous cell types.<ref name="Vincent">PMID:10390649</ref>

Only the C-terminal tail of NTS, amino acids 8-13, were resolved in the <scene name='72/721539/Nts8_13/2'>crystal structure</scene>.(PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]
== Structure ==
=== Overall Structure ===
[[Image:Nuerotensin membrane.jpg |100 px|left|thumb|Figure 1: Neurotensin Incorporation in Membrane ]]
Like other G protein-coupled receptors, the neurotensin receptor is composed of 3 distinct regions. An extracellular binding site where neurotensin binds and causes a conformational change of the protein. A region containing <scene name='72/727765/Overall_structure/4'>7 transmembrane alpha helices</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] that transduce the signal from the extracellular side of the cell membrane to the intracellular side. Lastly, an intracellular region that when activated by a conformational change in the protein activates a [https://en.wikipedia.org/wiki/G_protein G protein] associated with this receptor. Currently no crystal structures of the inactive form of the neurotensin receptor available. Without a representation of the inactive form, the conformational changes caused by agonist binding are still not completely known.
=== Neurotensin Binding Site ===
Binding of NTS to the binding site is enriched by <scene name='72/721539/Binding_pocket_surface/3'>charge complementarity</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]between the positive NTS arginine side chains and the [https://en.wikipedia.org/wiki/Electronegativity electronegative] pocket. In addition, the C-terminus forms a <scene name='72/721539/Binding_site_charges/2'>salt bridge</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] with R328. Only three out of eight [https://en.wikipedia.org/wiki/Hydrogen_bond hydrogen bonds] are made between the side chains of NTS and the receptor. Most of the interactions are [https://en.wikipedia.org/wiki/Van_der_Waals_force van der Waals] interactions. The binding pocket is partially capped by a [https://en.wikipedia.org/wiki/Beta_hairpin β-hairpin loop] at the proximal end of the receptor protein's N-terminus.<ref name="White"/>
=== Hydrophobic Stacking ===
A major player in the transduction of the extracellular signal to the intracellular G protein is the <scene name='72/727765/Hydrogen_bonding_network/1'>hydrogen bonding network</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]that links the bound hormone with the [https://en.wikipedia.org/wiki/Hydrophobe hydrophobic] core of the neurotensin receptor. The carboxylate of L13 forms a hydrogen bond network with R327, R328, and Y324. The Y324, in turn, is brought into an orientation to make the formation of a <scene name='72/727765/Hydrophobic_stacking_4xee/1'>hydrophobic stacking</scene> (PDB Code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE]) network between F358, W321, A157, and F317 possible.<ref name="Krumm">PMID:23051748</ref> The conformational changes caused by this stacking allows for the signal to be moved from the extracellular binding site through the transmembrane helices of the receptor to the intracellular region activating the G protein.
== Sodium Binding Pocket ==
Conserved across all class A GPCRs, a <scene name='72/727765/Gw5_na_pocket_final/2'>sodium ion-binding pocket</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] is seen in the middle of TM2 helix. The ion is coordinated with a highly conserved D2.50 and four other contacts with oxygen atoms. Some of these oxygen atoms are sourced from water molecules. In order for G-protein activation, a <scene name='72/721539/4xee_na_binding_pocket/1'>hydrogen bond network</scene> (PDB Code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE]) with T3.39, S7.46 ,N7.49 of the NPxxY [https://en.wikipedia.org/wiki/Structural_motif motif], prevents the coordination of a Na+. <ref name="Krumm"/><ref name="Katritch">PMID:24767681</ref>
=== Allosteric Effects ===
Sodium ions are a negative [https://en.wikipedia.org/wiki/Allosteric_regulation allosteric] inhibitor to the binding of the neurotensin [https://en.wikipedia.org/wiki/Agonist agonist] to the binding site on the neurotensin receptor. D113 of the highly conserved D/RY motif and N365 of the highly conserved NPxxY motif form a substantial hydrogen bonding network with T156 and S362.<ref name="Krumm"/> This hydrogen bonding network prevents the incorporation of the sodium ion by collapsing upon itself and therefor filling the sodium binding pocket. W321 also works to inhibit the incorporation of the sodium ion by capping off the sodium binding pocket to not allow sodium to enter from the top. W321 uses van der Walls interactions with other amino acids in the binding pocket to place it in the conformation necessary to complete this task.
==Clinical Relevance==
NTSR1 is commonly expressed in various invasive [https://en.wikipedia.org/wiki/Cancer cancer] cell lines. It is prevalent in the [https://en.wikipedia.org/wiki/Colorectal_cancer colon cancer] [https://en.wikipedia.org/wiki/Adenocarcinoma adenocarcinoma], but is not found in adult colon cell types. NTSR1 is also found in aggressive [https://en.wikipedia.org/wiki/Prostate_cancer prostate cancer] cells, but not [https://en.wikipedia.org/wiki/Epithelium epithelial] prostate cells. In prostate cancer cells, binding of the NTS results in [https://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase mitogen-activated protein kinase (PKB)], [https://en.wikipedia.org/wiki/Phosphoinositide_3-kinase phosphoinositide-3 kinase (PI-3K)], [https://en.wikipedia.org/wiki/Epidermal_growth_factor_receptor epidermal growth factor receptor (EGFR)], [https://en.wikipedia.org/wiki/Proto-oncogene_tyrosine-protein_kinase_Src SRC], and [https://en.wikipedia.org/wiki/STAT5 STAT5] phosphorylation. These all result in increased DNA sythesis, [https://en.wikipedia.org/wiki/Cell_growth cell proliferation], and survival. Inhibition of NTSR1 and its downstream signaling represents a target for [https://en.wikipedia.org/wiki/Radiation_therapy radiotherapy]. [[Image: Meclinerant.jpg |100 px|left|thumb|Meclinerant]]NTSR1 can be inhibited by agonist [https://en.wikipedia.org/wiki/Meclinertant meclinertant] which has shown evidence for the inhibition of proliferation and prosurvival of cancer cells. Treatment of radiation and meclinerant has shown to provide selective treatment of cancer cells over normal cells, indicating the need for clinical trials of this approach. <ref name="Valerie">PMID:21903767</ref> <ref name="Kisfalvi">PMID:19679549</ref>

</StructureSection>
== References ==
<references/>

Sandbox reserved 1169

2016-04-17T18:39:07Z

Andrew Koelper:

==Neurotensin Receptor (NTSR1)==
<StructureSection load='4GRV2.pdb' size='500' frame= 'true' align='right' caption='Neurotensin G-Protein Coupled Receptor (PDB Codes [http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV] and [http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE])' scene='72/727765/Overall_structure/2'/>__NoTOC__
== Introduction ==
The neurotensin receptor (NTSR1) belongs to the superfamily of proteins known as [http://proteopedia.org/wiki/index.php/G_protein-coupled_receptor G protein-coupled receptors] (GPCRs) and responds to the 13 amino acid hormone [https://en.wikipedia.org/wiki/Neurotensin neurotensin (NTS)]. Currently around 800 G protein-coupled receptors have been identified and are hypothesized to be responsible for roughly 80% of [https://en.wikipedia.org/wiki/Signal_transduction signal transduction].<ref name="Millar">PMID:20019124</ref> GPCRs are involved in a vast array of physiological processes within the body that range from interactions with [https://en.wikipedia.org/wiki/Dopamine dopamine] to effects on secretion of bile in the intestines.<ref name="Gui">PMID:11208724</ref> <ref name="Binder">PMID:1173461</ref> Due to the vast array of functions that these proteins serve and their high abundance within the body, these proteins have become major drug targets.<ref name="Fang">PMID:23573662</ref>

A critical topic in the understanding of GPCRs is the transition from the inactive to active state. This transition is responsible for the [https://en.wikipedia.org/wiki/Signal_transduction transduction] of a signal from the extracellular to the intracellular space. The transition occurs when a ligand, NTS in the case of NTSR1, binds to the receptor causing a [https://en.wikipedia.org/wiki/Conformational_change conformational change] in the protein that leads to the activation of the intracellular G protein. Currently no crystal structures of the receptor in its unbound, inactive form exist making the transition more difficult to study. <ref name="White">PMID:23051748</ref>
== Neurotensin ==
[https://en.wikipedia.org/wiki/Neurotensin Neurotensin (NTS)] is a 13-amino acid peptide originally isolated from [https://en.wikipedia.org/w/index.php?title=Bovinae&redirect=no bovine] [https://en.wikipedia.org/wiki/Hypothalamus hypothalamus]. NTS fulfills the roles of both a [https://en.wikipedia.org/wiki/Neurotransmitter neurotransmitter] and a [https://en.wikipedia.org/wiki/Neuromodulation neuromodulator] in the nervous system and a [https://en.wikipedia.org/wiki/Hormone hormone] in the periphery nervous system. NTS is a neuromodulator of dopamine transmission and of anterior [https://en.wikipedia.org/wiki/Pituitary_gland pituitary] hormone secretion. In the periphery of the digestive tract and cardiovascular system, NTS is a [https://en.wikipedia.org/w/index.php?title=Paracrine_signalling&redirect=no paracrine] and [https://en.wikipedia.org/wiki/Endocrine_system endocrine] modulator. Finally, NTS serves as a [https://en.wikipedia.org/wiki/Growth_factor growth factor] for many normal and cancerous cell types.<ref name="Vincent">PMID:10390649</ref>

Only the C-terminal tail of NTS, amino acids 8-13, were resolved in the <scene name='72/721539/Nts8_13/2'>crystal structure</scene>.(PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]
== Structure ==
=== Overall Structure ===
[[Image:Nuerotensin membrane.jpg |100 px|left|thumb|Figure 1: Neurotensin Incorporation in Membrane ]]
Like other G protein-coupled receptors, the neurotensin receptor is composed of 3 distinct regions. An extracellular binding site where neurotensin binds and causes a conformational change of the protein. A region containing <scene name='72/727765/Overall_structure/4'>7 transmembrane alpha helices</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] that transduce the signal from the extracellular side of the cell membrane to the intracellular side. Lastly, an intracellular region that when activated by a conformational change in the protein activates a [https://en.wikipedia.org/wiki/G_protein G protein] associated with this receptor. Currently no crystal structures of the inactive form of the neurotensin receptor available. Without a representation of the inactive form, the conformational changes caused by agonist binding are still not completely known.
=== Neurotensin Binding Site ===
Binding of NTS to the binding site is enriched by <scene name='72/721539/Binding_pocket_surface/3'>charge complementarity</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]between the positive NTS arginine side chains and the [https://en.wikipedia.org/wiki/Electronegativity electronegative] pocket. In addition, the C-terminus forms a <scene name='72/721539/Binding_site_charges/2'>salt bridge</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] with R328. Only three out of eight [https://en.wikipedia.org/wiki/Hydrogen_bond hydrogen bonds] are made between the side chains of NTS and the receptor. Most of the interactions are [https://en.wikipedia.org/wiki/Van_der_Waals_force van der Waals] interactions. The binding pocket is partially capped by a [https://en.wikipedia.org/wiki/Beta_hairpin β-hairpin loop] at the proximal end of the receptor protein's N-terminus.<ref name="White"/>
=== Hydrophobic Stacking ===
A major player in the transduction of the extracellular signal to the intracellular G protein is the <scene name='72/727765/Hydrogen_bonding_network/1'>hydrogen bonding network</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]that links the bound hormone with the [https://en.wikipedia.org/wiki/Hydrophobe hydrophobic] core of the neurotensin receptor. The carboxylate of L13 forms a hydrogen bond network with R327, R328, and Y324. The Y324, in turn, is brought into an orientation to make the formation of a <scene name='72/727765/Hydrophobic_stacking_4xee/1'>hydrophobic stacking</scene> (PDB Code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE]) network between F358, W321, A157, and F317 possible.<ref name="Krumm">PMID:23051748</ref> The conformational changes caused by this stacking allows for the signal to be moved from the extracellular binding site through the transmembrane helices of the receptor to the intracellular region activating the G protein.
== Sodium Binding Pocket ==
Conserved across all class A GPCRs, a <scene name='72/727765/Gw5_na_pocket_final/2'>sodium ion-binding pocket</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] is seen in the middle of TM2 helix. The ion is coordinated with a highly conserved D2.50 and four other contacts with oxygen atoms. Some of these oxygen atoms are sourced from water molecules. In order for G-protein activation, a <scene name='72/721539/4xee_na_binding_pocket/1'>hydrogen bond network</scene> (PDB Code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE]) with T3.39, S7.46 ,N7.49 of the NPxxY [https://en.wikipedia.org/wiki/Structural_motif motif], prevents the coordination of a Na+. <ref name="Krumm"/><ref name="Katritch">PMID:24767681</ref>
=== Allosteric Effects ===
Sodium ions are a negative [https://en.wikipedia.org/wiki/Allosteric_regulation allosteric] inhibitor to the binding of the neurotensin [https://en.wikipedia.org/wiki/Agonist agonist] to the binding site on the neurotensin receptor. D113 of the highly conserved D/RY motif and N365 of the highly conserved NPxxY motif form a substantial hydrogen bonding network with T156 and S362.<ref name="Krumm"/> This hydrogen bonding network prevents the incorporation of the sodium ion by collapsing upon itself and therefor filling the sodium binding pocket. W321 also works to inhibit the incorporation of the sodium ion by capping off the sodium binding pocket to not allow sodium to enter from the top. W321 uses van der Walls interactions with other amino acids in the binding pocket to place it in the conformation necessary to complete this task.
==Clinical Relevance==
NTSR1 is commonly expressed in various invasive [https://en.wikipedia.org/wiki/Cancer cancer] cell lines. It is prevalent in the [https://en.wikipedia.org/wiki/Colorectal_cancer colon cancer] [https://en.wikipedia.org/wiki/Adenocarcinoma adenocarcinoma], but is not found in adult colon cell types. NTSR1 is also found in aggressive [https://en.wikipedia.org/wiki/Prostate_cancer prostate cancer] cells, but not [https://en.wikipedia.org/wiki/Epithelium epithelial] prostate cells. In prostate cancer cells, binding of the NTS results in [https://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase mitogen-activated protein kinase (PKB)], [https://en.wikipedia.org/wiki/Phosphoinositide_3-kinase phosphoinositide-3 kinase (PI-3K)], [https://en.wikipedia.org/wiki/Epidermal_growth_factor_receptor epidermal growth factor receptor (EGFR)], [https://en.wikipedia.org/wiki/Proto-oncogene_tyrosine-protein_kinase_Src SRC], and [https://en.wikipedia.org/wiki/STAT5 STAT5] phosphorylation. These all result in increased DNA sythesis, [https://en.wikipedia.org/wiki/Cell_growth cell proliferation], and survival. Inhibition of NTSR1 and its downstream signaling represents a target for [https://en.wikipedia.org/wiki/Radiation_therapy radiotherapy]. [[Image: Meclinerant.jpg |100 px|left|thumb|Meclinerant]]NTSR1 can be inhibited by agonist [https://en.wikipedia.org/wiki/Meclinertant meclinertant] which has shown evidence for the inhibition of proliferation and prosurvival of cancer cells. Treatment of radiation and meclinerant has shown to provide selective treatment of cancer cells over normal cells, indicating the need for clinical trials of this approach. <ref name="Valerie">PMID:21903767</ref> <ref name="Kisfalvi">PMID:19679549</ref>

</StructureSection>
== References ==
<references/>

Sandbox reserved 1169

2016-04-17T18:33:34Z

Andrew Koelper:

==Neurotensin Receptor (NTSR1)==
<StructureSection load='4GRV2.pdb' size='340' frame= 'true' align='right' caption='Neurotensin G-Protein Coupled Receptor (PDB Codes [http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV] and [http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE])' scene='72/727765/Overall_structure/2'/>
== Introduction ==
The neurotensin receptor (NTSR1) belongs to the superfamily of proteins known as [http://proteopedia.org/wiki/index.php/G_protein-coupled_receptor G protein-coupled receptors] (GPCRs) and responds to the 13 amino acid hormone [https://en.wikipedia.org/wiki/Neurotensin neurotensin (NTS)]. Currently around 800 G protein-coupled receptors have been identified and are hypothesized to be responsible for roughly 80% of [https://en.wikipedia.org/wiki/Signal_transduction signal transduction].<ref name="Millar">PMID:20019124</ref> GPCRs are involved in a vast array of physiological processes within the body that range from interactions with [https://en.wikipedia.org/wiki/Dopamine dopamine] to effects on secretion of bile in the intestines.<ref name="Gui">PMID:11208724</ref> <ref name="Binder">PMID:1173461</ref> Due to the vast array of functions that these proteins serve and their high abundance within the body, these proteins have become major drug targets.<ref name="Fang">PMID:23573662</ref>

A critical topic in the understanding of GPCRs is the transition from the inactive to active state. This transition is responsible for the [https://en.wikipedia.org/wiki/Signal_transduction transduction] of a signal from the extracellular to the intracellular space. The transition occurs when a ligand, NTS in the case of NTSR1, binds to the receptor causing a [https://en.wikipedia.org/wiki/Conformational_change conformational change] in the protein that leads to the activation of the intracellular G protein. Currently no crystal structures of the receptor in its unbound, inactive form exist making the transition more difficult to study. <ref name="White">PMID:23051748</ref>
== Neurotensin ==
[https://en.wikipedia.org/wiki/Neurotensin Neurotensin (NTS)] is a 13-amino acid peptide originally isolated from [https://en.wikipedia.org/w/index.php?title=Bovinae&redirect=no bovine] [https://en.wikipedia.org/wiki/Hypothalamus hypothalamus]. NTS fulfills the roles of both a [https://en.wikipedia.org/wiki/Neurotransmitter neurotransmitter] and a [https://en.wikipedia.org/wiki/Neuromodulation neuromodulator] in the nervous system and a [https://en.wikipedia.org/wiki/Hormone hormone] in the periphery nervous system. NTS is a neuromodulator of dopamine transmission and of anterior [https://en.wikipedia.org/wiki/Pituitary_gland pituitary] hormone secretion. In the periphery of the digestive tract and cardiovascular system, NTS is a [https://en.wikipedia.org/w/index.php?title=Paracrine_signalling&redirect=no paracrine] and [https://en.wikipedia.org/wiki/Endocrine_system endocrine] modulator. Finally, NTS serves as a [https://en.wikipedia.org/wiki/Growth_factor growth factor] for many normal and cancerous cell types.<ref name="Vincent">PMID:10390649</ref>

Only the C-terminal tail of NTS, amino acids 8-13, were resolved in the <scene name='72/721539/Nts8_13/2'>crystal structure</scene>.(PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]
== Structure ==
=== Overall Structure ===
<StructureSection load='4GRV2.pdb' size='340' frame= 'true' align='right' caption='Neurotensin G-Protein Coupled Receptor (PDB Codes [http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV] and [http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE])' scene='72/727765/Overall_structure/2'/>
[[Image:Nuerotensin membrane.jpg |100 px|left|thumb|Figure 1: Neurotensin Incorporation in Membrane ]]
Like other G protein-coupled receptors, the neurotensin receptor is composed of 3 distinct regions. An extracellular binding site where neurotensin binds and causes a conformational change of the protein. A region containing <scene name='72/727765/Overall_structure/4'>7 transmembrane alpha helices</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] that transduce the signal from the extracellular side of the cell membrane to the intracellular side. Lastly, an intracellular region that when activated by a conformational change in the protein activates a [https://en.wikipedia.org/wiki/G_protein G protein] associated with this receptor. Currently no crystal structures of the inactive form of the neurotensin receptor available. Without a representation of the inactive form, the conformational changes caused by agonist binding are still not completely known.
=== Neurotensin Binding Site ===
Binding of NTS to the binding site is enriched by <scene name='72/721539/Binding_pocket_surface/3'>charge complementarity</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]between the positive NTS arginine side chains and the [https://en.wikipedia.org/wiki/Electronegativity electronegative] pocket. In addition, the C-terminus forms a <scene name='72/721539/Binding_site_charges/2'>salt bridge</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] with R328. Only three out of eight [https://en.wikipedia.org/wiki/Hydrogen_bond hydrogen bonds] are made between the side chains of NTS and the receptor. Most of the interactions are [https://en.wikipedia.org/wiki/Van_der_Waals_force van der Waals] interactions. The binding pocket is partially capped by a [https://en.wikipedia.org/wiki/Beta_hairpin β-hairpin loop] at the proximal end of the receptor protein's N-terminus.<ref name="White"/>
=== Hydrophobic Stacking ===
A major player in the transduction of the extracellular signal to the intracellular G protein is the <scene name='72/727765/Hydrogen_bonding_network/1'>hydrogen bonding network</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]that links the bound hormone with the [https://en.wikipedia.org/wiki/Hydrophobe hydrophobic] core of the neurotensin receptor. The carboxylate of L13 forms a hydrogen bond network with R327, R328, and Y324. The Y324, in turn, is brought into an orientation to make the formation of a <scene name='72/727765/Hydrophobic_stacking_4xee/1'>hydrophobic stacking</scene> (PDB Code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE]) network between F358, W321, A157, and F317 possible.<ref name="Krumm">PMID:23051748</ref> The conformational changes caused by this stacking allows for the signal to be moved from the extracellular binding site through the transmembrane helices of the receptor to the intracellular region activating the G protein.
== Sodium Binding Pocket ==
Conserved across all class A GPCRs, a <scene name='72/727765/Gw5_na_pocket_final/2'>sodium ion-binding pocket</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] is seen in the middle of TM2 helix. The ion is coordinated with a highly conserved D2.50 and four other contacts with oxygen atoms. Some of these oxygen atoms are sourced from water molecules. In order for G-protein activation, a <scene name='72/721539/4xee_na_binding_pocket/1'>hydrogen bond network</scene> (PDB Code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE]) with T3.39, S7.46 ,N7.49 of the NPxxY [https://en.wikipedia.org/wiki/Structural_motif motif], prevents the coordination of a Na+. <ref name="Krumm"/><ref name="Katritch">PMID:24767681</ref>
=== Allosteric Effects ===
Sodium ions are a negative [https://en.wikipedia.org/wiki/Allosteric_regulation allosteric] inhibitor to the binding of the neurotensin [https://en.wikipedia.org/wiki/Agonist agonist] to the binding site on the neurotensin receptor. D113 of the highly conserved D/RY motif and N365 of the highly conserved NPxxY motif form a substantial hydrogen bonding network with T156 and S362.<ref name="Krumm"/> This hydrogen bonding network prevents the incorporation of the sodium ion by collapsing upon itself and therefor filling the sodium binding pocket. W321 also works to inhibit the incorporation of the sodium ion by capping off the sodium binding pocket to not allow sodium to enter from the top. W321 uses van der Walls interactions with other amino acids in the binding pocket to place it in the conformation necessary to complete this task.
==Clinical Relevance==
NTSR1 is commonly expressed in various invasive [https://en.wikipedia.org/wiki/Cancer cancer] cell lines. It is prevalent in the [https://en.wikipedia.org/wiki/Colorectal_cancer colon cancer] [https://en.wikipedia.org/wiki/Adenocarcinoma adenocarcinoma], but is not found in adult colon cell types. NTSR1 is also found in aggressive [https://en.wikipedia.org/wiki/Prostate_cancer prostate cancer] cells, but not [https://en.wikipedia.org/wiki/Epithelium epithelial] prostate cells. In prostate cancer cells, binding of the NTS results in [https://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase mitogen-activated protein kinase (PKB)], [https://en.wikipedia.org/wiki/Phosphoinositide_3-kinase phosphoinositide-3 kinase (PI-3K)], [https://en.wikipedia.org/wiki/Epidermal_growth_factor_receptor epidermal growth factor receptor (EGFR)], [https://en.wikipedia.org/wiki/Proto-oncogene_tyrosine-protein_kinase_Src SRC], and [https://en.wikipedia.org/wiki/STAT5 STAT5] phosphorylation. These all result in increased DNA sythesis, [https://en.wikipedia.org/wiki/Cell_growth cell proliferation], and survival. Inhibition of NTSR1 and its downstream signaling represents a target for [https://en.wikipedia.org/wiki/Radiation_therapy radiotherapy]. [[Image: Meclinerant.jpg |100 px|left|thumb|Meclinerant]]NTSR1 can be inhibited by agonist [https://en.wikipedia.org/wiki/Meclinertant meclinertant] which has shown evidence for the inhibition of proliferation and prosurvival of cancer cells. Treatment of radiation and meclinerant has shown to provide selective treatment of cancer cells over normal cells, indicating the need for clinical trials of this approach. <ref name="Valerie">PMID:21903767</ref> <ref name="Kisfalvi">PMID:19679549</ref>

</StructureSection>
== References ==
<references/>

Sandbox reserved 1169

2016-04-17T18:23:40Z

Andrew Koelper:

==Neurotensin Receptor (NTSR1)==
<StructureSection load='4GRV2.pdb' size='340' frame= 'true' align='right' caption='Neurotensin G-Protein Coupled Receptor (PDB Codes [http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV] and [http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE])' scene='72/727765/Overall_structure/2'/>
== Introduction ==
The neurotensin receptor (NTSR1) belongs to the superfamily of proteins known as [http://proteopedia.org/wiki/index.php/G_protein-coupled_receptor G protein-coupled receptors] (GPCRs) and responds to the 13 amino acid hormone [https://en.wikipedia.org/wiki/Neurotensin neurotensin (NTS)]. Currently around 800 G protein-coupled receptors have been identified and are hypothesized to be responsible for roughly 80% of [https://en.wikipedia.org/wiki/Signal_transduction signal transduction].<ref name="Millar">PMID:20019124</ref> GPCRs are involved in a vast array of physiological processes within the body that range from interactions with [https://en.wikipedia.org/wiki/Dopamine dopamine] to effects on secretion of bile in the intestines.<ref name="Gui">PMID:11208724</ref> <ref name="Binder">PMID:1173461</ref> Due to the vast array of functions that these proteins serve and their high abundance within the body, these proteins have become major drug targets.<ref name="Fang">PMID:23573662</ref>

A critical topic in the understanding of GPCRs is the transition from the inactive to active state. This transition is responsible for the [https://en.wikipedia.org/wiki/Signal_transduction transduction] of a signal from the extracellular to the intracellular space. The transition occurs when a ligand, NTS in the case of NTSR1, binds to the receptor causing a [https://en.wikipedia.org/wiki/Conformational_change conformational change] in the protein that leads to the activation of the intracellular G protein. Currently no crystal structures of the receptor in its unbound, inactive form exist making the transition more difficult to study. <ref name="White">PMID:23051748</ref>
== Neurotensin ==
[https://en.wikipedia.org/wiki/Neurotensin Neurotensin (NTS)] is a 13-amino acid peptide originally isolated from [https://en.wikipedia.org/w/index.php?title=Bovinae&redirect=no bovine] [https://en.wikipedia.org/wiki/Hypothalamus hypothalamus]. NTS fulfills the roles of both a [https://en.wikipedia.org/wiki/Neurotransmitter neurotransmitter] and a [https://en.wikipedia.org/wiki/Neuromodulation neuromodulator] in the nervous system and a [https://en.wikipedia.org/wiki/Hormone hormone] in the periphery nervous system. NTS is a neuromodulator of dopamine transmission and of anterior [https://en.wikipedia.org/wiki/Pituitary_gland pituitary] hormone secretion. In the periphery of the digestive tract and cardiovascular system, NTS is a [https://en.wikipedia.org/w/index.php?title=Paracrine_signalling&redirect=no paracrine] and [https://en.wikipedia.org/wiki/Endocrine_system endocrine] modulator. Finally, NTS serves as a [https://en.wikipedia.org/wiki/Growth_factor growth factor] for many normal and cancerous cell types.<ref name="Vincent">PMID:10390649</ref>

Only the C-terminal tail of NTS, amino acids 8-13, were resolved in the <scene name='72/721539/Nts8_13/2'>crystal structure</scene>.(PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]
== Structure ==
=== Overall Structure ===
[[Image:Nuerotensin membrane.jpg |100 px|left|thumb|Figure 1: Neurotensin Incorporation in Membrane ]]
Like other G protein-coupled receptors, the neurotensin receptor is composed of 3 distinct regions. An extracellular binding site where neurotensin binds and causes a conformational change of the protein. A region containing <scene name='72/727765/Overall_structure/1'>7 transmembrane alpha helices</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] that transduce the signal from the extracellular side of the cell membrane to the intracellular side. Lastly, an intracellular region that when activated by a conformational change in the protein activates a [https://en.wikipedia.org/wiki/G_protein G protein] associated with this receptor. Currently no crystal structures of the inactive form of the neurotensin receptor available. Without a representation of the inactive form, the conformational changes caused by agonist binding are still not completely known.
=== Neurotensin Binding Site ===
Binding of NTS to the binding site is enriched by <scene name='72/721539/Binding_pocket_surface/3'>charge complementarity</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]between the positive NTS arginine side chains and the [https://en.wikipedia.org/wiki/Electronegativity electronegative] pocket. In addition, the C-terminus forms a <scene name='72/721539/Binding_site_charges/2'>salt bridge</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] with R328. Only three out of eight [https://en.wikipedia.org/wiki/Hydrogen_bond hydrogen bonds] are made between the side chains of NTS and the receptor. Most of the interactions are [https://en.wikipedia.org/wiki/Van_der_Waals_force van der Waals] interactions. The binding pocket is partially capped by a [https://en.wikipedia.org/wiki/Beta_hairpin β-hairpin loop] at the proximal end of the receptor protein's N-terminus.<ref name="White"/>
=== Hydrophobic Stacking ===
A major player in the transduction of the extracellular signal to the intracellular G protein is the <scene name='72/727765/Hydrogen_bonding_network/1'>hydrogen bonding network</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]that links the bound hormone with the [https://en.wikipedia.org/wiki/Hydrophobe hydrophobic] core of the neurotensin receptor. The carboxylate of L13 forms a hydrogen bond network with R327, R328, and Y324. The Y324, in turn, is brought into an orientation to make the formation of a <scene name='72/727765/Hydrophobic_stacking_4xee/1'>hydrophobic stacking</scene> (PDB Code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE]) network between F358, W321, A157, and F317 possible.<ref name="Krumm">PMID:23051748</ref> The conformational changes caused by this stacking allows for the signal to be moved from the extracellular binding site through the transmembrane helices of the receptor to the intracellular region activating the G protein.
== Sodium Binding Pocket ==
Conserved across all class A GPCRs, a <scene name='72/727765/Gw5_na_pocket_final/2'>sodium ion-binding pocket</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] is seen in the middle of TM2 helix. The ion is coordinated with a highly conserved D2.50 and four other contacts with oxygen atoms. Some of these oxygen atoms are sourced from water molecules. In order for G-protein activation, a <scene name='72/721539/4xee_na_binding_pocket/1'>hydrogen bond network</scene> (PDB Code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE]) with T3.39, S7.46 ,N7.49 of the NPxxY [https://en.wikipedia.org/wiki/Structural_motif motif], prevents the coordination of a Na+. <ref name="Krumm"/><ref name="Katritch">PMID:24767681</ref>
=== Allosteric Effects ===
Sodium ions are a negative [https://en.wikipedia.org/wiki/Allosteric_regulation allosteric] inhibitor to the binding of the neurotensin [https://en.wikipedia.org/wiki/Agonist agonist] to the binding site on the neurotensin receptor. D113 of the highly conserved D/RY motif and N365 of the highly conserved NPxxY motif form a substantial hydrogen bonding network with T156 and S362.<ref name="Krumm"/> This hydrogen bonding network prevents the incorporation of the sodium ion by collapsing upon itself and therefor filling the sodium binding pocket. W321 also works to inhibit the incorporation of the sodium ion by capping off the sodium binding pocket to not allow sodium to enter from the top. W321 uses van der Walls interactions with other amino acids in the binding pocket to place it in the conformation necessary to complete this task.
==Clinical Relevance==
NTSR1 is commonly expressed in various invasive [https://en.wikipedia.org/wiki/Cancer cancer] cell lines. It is prevalent in the [https://en.wikipedia.org/wiki/Colorectal_cancer colon cancer] [https://en.wikipedia.org/wiki/Adenocarcinoma adenocarcinoma], but is not found in adult colon cell types. NTSR1 is also found in aggressive [https://en.wikipedia.org/wiki/Prostate_cancer prostate cancer] cells, but not [https://en.wikipedia.org/wiki/Epithelium epithelial] prostate cells. In prostate cancer cells, binding of the NTS results in [https://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase mitogen-activated protein kinase (PKB)], [https://en.wikipedia.org/wiki/Phosphoinositide_3-kinase phosphoinositide-3 kinase (PI-3K)], [https://en.wikipedia.org/wiki/Epidermal_growth_factor_receptor epidermal growth factor receptor (EGFR)], [https://en.wikipedia.org/wiki/Proto-oncogene_tyrosine-protein_kinase_Src SRC], and [https://en.wikipedia.org/wiki/STAT5 STAT5] phosphorylation. These all result in increased DNA sythesis, [https://en.wikipedia.org/wiki/Cell_growth cell proliferation], and survival. Inhibition of NTSR1 and its downstream signaling represents a target for [https://en.wikipedia.org/wiki/Radiation_therapy radiotherapy]. [[Image: Meclinerant.jpg |100 px|left|thumb|Meclinerant]]NTSR1 can be inhibited by agonist [https://en.wikipedia.org/wiki/Meclinertant meclinertant] which has shown evidence for the inhibition of proliferation and prosurvival of cancer cells. Treatment of radiation and meclinerant has shown to provide selective treatment of cancer cells over normal cells, indicating the need for clinical trials of this approach. <ref name="Valerie">PMID:21903767</ref> <ref name="Kisfalvi">PMID:19679549</ref>

</StructureSection>
== References ==
<references/>

Sandbox Reserved 1168

2016-04-12T13:16:18Z

Andrew Koelper:

{{Sandbox_Reserved_CH462_Central_Metabolism}}
==Structure==
<StructureSection load='4GRV2.pdb' size='340' frame= 'true' align='right' caption='Neurotensin G-Protein Coupled Receptor (PDB Codes [http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV] and [http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE])' scene='72/727765/Overall_structure/2'/>
== Neurotensin==
<scene name='72/721539/Nts8_13/1'>Neurotensin(NTS)</scene> is a 13-amino acid peptide originally isolated from bovine hypothalamus. It fulfills the role of both a neurotransmitter and a neuromodulator in the nervous system and a hormone in the periphery. NTS is a neuromodulator of dopamine transmission and of anterior pituitary hormone secretion. It is also a paracrine and endocrine modulator in the periphery of the digestive tract and cardiovascular system. Finally, NTS serves as a growth factor for many normal and cancerous cell types.(Vincent)

Only the C-terminal tail of NTS, amino acids 8-13, were resolved in the crystal structure.
<scene name='72/727765/Overall_structure/4'>TextToBeDisplayed</scene>
== Binding Site ==
Binding of NTS to the binding site is enriched by <scene name='72/721539/Binding_pocket_surface/3'>charge complementarity</scene> between the positive NTS arginine side chains and the electronegative pocket. In addition, the C-terminus forms a <scene name='72/721539/Binding_site_charges/2'>salt bridge</scene> with R328. Only three out of eight hydrogen bonds are made between the side chains of NTS and the receptor. Most of the interactions are van der Waals interactions. The binding pocket is partially capped by a hairpin loop at the proximal end of the receptor protein's N-terminus. (White)

== Na+ Binding Site ==
Conserved across all class A GPCRs, a sodium ion-binding pocket is seen in the middle of TM2 helix. The ion is coordinated with a highly conserved D2.50 and four other contacts with oxygen atoms. Some of these oxygen atoms are sourced from water molecules. In order for G-protein activation, a hydrogen bond network with T3.39, S7.46 ,N7.49 of the NPxxY motif, prevents the coordination of a Na+.

== Function ==

<scene name='72/721539/4xee_na_binding_pocket/1'>4xee Sodium Binding Pocket</scene>
== Disease ==

== Relevance ==

== Structural highlights ==

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.

</StructureSection>
== References ==
<references/>

Sandbox Reserved 1168

2016-04-12T12:37:38Z

Andrew Koelper:

{{Sandbox_Reserved_CH462_Central_Metabolism}}
==Structure==
<StructureSection load='4GRV2.pdb' size='340' frame= 'true' align='right' caption='Neurotensin G-Protein Coupled Receptor (PDB Codes [http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV] and [http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE])' scene='72/727765/Overall_structure/2'/>
== Neurotensin==
<scene name='72/721539/Nts8_13/1'>Neurotensin(NTS)</scene> is a 13-amino acid peptide originally isolated from bovine hypothalamus. It fulfills the role of both a neurotransmitter and a neuromodulator in the nervous system and a hormone in the periphery. NTS is a neuromodulator of dopamine transmission and of anterior pituitary hormone secretion. It is also a paracrine and endocrine modulator in the periphery of the digestive tract and cardiovascular system. Finally, NTS serves as a growth factor for many normal and cancerous cell types.(Vincent)

Only the C-terminal tail of NTS, amino acids 8-13, were resolved in the crystal structure.

== Binding Site ==
Binding of NTS to the binding site is enriched by <scene name='72/721539/Binding_pocket_surface/3'>charge complementarity</scene> between the positive NTS arginine side chains and the electronegative pocket. In addition, the C-terminus forms a <scene name='72/721539/Binding_site_charges/2'>salt bridge</scene> with R328. Only three out of eight hydrogen bonds are made between the side chains of NTS and the receptor. Most of the interactions are van der Waals interactions. The binding pocket is partially capped by a hairpin loop at the proximal end of the receptor protein's N-terminus. (White)

== Na+ Binding Site ==
Conserved across all class A GPCRs, a sodium ion-binding pocket is seen in the middle of TM2 helix. The ion is coordinated with a highly conserved D2.50 and four other contacts with oxygen atoms. Some of these oxygen atoms are sourced from water molecules. In order for G-protein activation, a hydrogen bond network with T3.39, S7.46 ,N7.49 of the NPxxY motif, prevents the coordination of a Na+.

== Function ==

<scene name='72/721539/4xee_na_binding_pocket/1'>4xee Sodium Binding Pocket</scene>
== Disease ==

== Relevance ==

== Structural highlights ==

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.

</StructureSection>
== References ==
<references/>

Sandbox reserved 1169

2016-04-12T12:34:27Z

Andrew Koelper:

==Neurotensin Receptor (''Rattus norvegicus'')==
<StructureSection load='4GRV2.pdb' size='340' frame= 'true' align='right' caption='Neurotensin G-Protein Coupled Receptor (PDB Codes [http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV] and [http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE])' scene='72/727765/Overall_structure/2'/>
== Introduction ==
The neurotensin receptor (NTSR1) belongs to the superfamily of proteins known as [http://proteopedia.org/wiki/index.php/G_protein-coupled_receptor G protein-coupled receptors] (GPCRs) and responds to the 13 amino acid hormone [https://en.wikipedia.org/wiki/Neurotensin neurotensin (NTS)]. There are currently around 800 G protein-coupled receptors that have been identified and are thought to be responsible for roughly 80% of [https://en.wikipedia.org/wiki/Signal_transduction signal transduction] across the cell membrane.<ref name="Millar">PMID:20019124</ref> These receptors are involved in a vast array of physiological processes within the body that range from interactions with [https://en.wikipedia.org/wiki/Dopamine dopamine] to effects on secretion of bile in the intestines.<ref name="Gui">PMID:11208724</ref> <ref name="Binder">PMID:1173461</ref> Due to the vast array of functions that these proteins serve and their high abundance within the body, these proteins have become a major site of drug targets in medicine making a deeper, more in depth understanding of these proteins very important. <ref name="Fang">PMID:23573662</ref> There are currently no NTRS1 structures of the inactive state, so there is no way to determine the [https://en.wikipedia.org/wiki/Conformational_change conformational change] of the binding pocket caused by the binding of NTS. <ref name="White">PMID:23051748</ref>
== Neurotensin ==
[https://en.wikipedia.org/wiki/Neurotensin Neurotensin (NTS)] is a 13-amino acid peptide originally isolated from [https://en.wikipedia.org/w/index.php?title=Bovinae&redirect=no bovine] [https://en.wikipedia.org/wiki/Hypothalamus hypothalamus]. It fulfills the role of both a [https://en.wikipedia.org/wiki/Neurotransmitter neurotransmitter] and a [https://en.wikipedia.org/wiki/Neuromodulation neuromodulator] in the nervous system and a [https://en.wikipedia.org/wiki/Hormone hormone] in the periphery. NTS is a neuromodulator of dopamine transmission and of anterior [https://en.wikipedia.org/wiki/Pituitary_gland pituitary] hormone secretion. It is also a [https://en.wikipedia.org/w/index.php?title=Paracrine_signalling&redirect=no paracrine] and [https://en.wikipedia.org/wiki/Endocrine_system endocrine] modulator in the periphery of the digestive tract and cardiovascular system. Finally, NTS serves as a [https://en.wikipedia.org/wiki/Growth_factor growth factor] for many normal and cancerous cell types.<ref name="Vincent">PMID:10390649</ref>

Only the C-terminal tail of NTS, amino acids 8-13, were resolved in the <scene name='72/721539/Nts8_13/1'>crystal structure</scene>.(PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]
== Structure ==
=== Overall Structure ===
[[Image:Nuerotensin membrane.jpg |100 px|left|thumb|Neurotensin Incorporation in Membrane ]]
Like other G protein-coupled receptors, the neurotensin receptor is composed of 3 distinct regions. An extracellular binding site where neurotensin binds and causes a conformational change of the protein, a region containing <scene name='72/727765/Overall_structure/1'>7 transmembrane alpha helices</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] that transduce the signal from the extracellular side of the cell membrane to the intracellular side, and an intracellular region that, when activated by a conformational change in the protein, activates a [https://en.wikipedia.org/wiki/G_protein G protein] associated with this receptor. There are currently no crystal structures of the inactive form of the neurotensin receptor available. Without a representation of the inactive form, the conformational changes caused by agonist binding are still not completely known.
=== Neurotensin Binding Site ===
Binding of NTS to the binding site is enriched by <scene name='72/721539/Binding_pocket_surface/3'>charge complementarity</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]between the positive NTS arginine side chains and the [https://en.wikipedia.org/wiki/Electronegativity electronegative] pocket. In addition, the C-terminus forms a <scene name='72/721539/Binding_site_charges/2'>salt bridge</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] with R328. Only three out of eight [https://en.wikipedia.org/wiki/Hydrogen_bond hydrogen bonds] are made between the side chains of NTS and the receptor. Most of the interactions are [https://en.wikipedia.org/wiki/Van_der_Waals_force van der Waals] interactions. The binding pocket is partially capped by a [https://en.wikipedia.org/wiki/Beta_hairpin β-hairpin loop] at the proximal end of the receptor protein's N-terminus.<ref name="White"/>
=== Hydrophobic Stacking ===
A major player in the transduction of the extracellular signal to the intracellular G protein is the <scene name='72/727765/Hydrogen_bonding_network/1'>hydrogen bonding network</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]that links the bound hormone with the [https://en.wikipedia.org/wiki/Hydrophobe hydrophobic] core of the neurotensin receptor. The carboxylate of L13 forms a hydrogen bond network with R327, R328, and Y324. The Y324, in turn, is brought into an orientation to make the formation of a <scene name='72/727765/Hydrophobic_stacking_4xee/1'>hydrophobic stacking</scene> (PDB Code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE]) network between F358, W321, A157, and F317 possible.<ref name="Krumm">PMID:23051748</ref> The conformational changes caused by this stacking allows for the signal to be moved from the extracellular binding site through the transmembrane helices of the receptor to the intracellular region activating the G protein.
== Sodium Binding Pocket ==
Conserved across all class A GPCRs, a <scene name='72/727765/Gw5_na_pocket_final/2'>sodium ion-binding pocket</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] is seen in the middle of TM2 helix. The ion is coordinated with a highly conserved D2.50 and four other contacts with oxygen atoms. Some of these oxygen atoms are sourced from water molecules. In order for G-protein activation, a <scene name='72/721539/4xee_na_binding_pocket/1'>hydrogen bond network</scene> (PDB Code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE]) with T3.39, S7.46 ,N7.49 of the NPxxY [https://en.wikipedia.org/wiki/Structural_motif motif], prevents the coordination of a Na+. <ref name="Krumm"/><ref name="Katritch">PMID:24767681</ref>
=== Allosteric Effects ===
Sodium ions are a negative [https://en.wikipedia.org/wiki/Allosteric_regulation allosteric] inhibitor to the binding of the neurotensin [https://en.wikipedia.org/wiki/Agonist agonist] to the binding site on the neurotensin receptor. D113 of the highly conserved D/RY motif and N365 of the highly conserved NPxxY motif form a substantial hydrogen bonding network with T156 and S362.<ref name="Krumm"/> This hydrogen bonding network prevents the incorporation of the sodium ion by collapsing upon itself and therefor filling the sodium binding pocket. W321 also works to inhibit the incorporation of the sodium ion by capping off the sodium binding pocket to not allow sodium to enter from the top. W321 uses van der Walls interactions with other amino acids in the binding pocket to place it in the conformation necessary to complete this task.
==Clinical Relevance==
NTSR1 is commonly expressed in various invasive [https://en.wikipedia.org/wiki/Cancer cancer] cell lines. It is prevalent in the [https://en.wikipedia.org/wiki/Colorectal_cancer colon cancer] [https://en.wikipedia.org/wiki/Adenocarcinoma adenocarcinoma], but is not found in adult colon cell types. NTSR1 is also found in aggressive [https://en.wikipedia.org/wiki/Prostate_cancer prostate cancer] cells, but not [https://en.wikipedia.org/wiki/Epithelium epithelial] prostate cells. In prostate cancer cells, binding of the NTS results in [https://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase mitogen-activated protein kinase (PKB)], [https://en.wikipedia.org/wiki/Phosphoinositide_3-kinase phosphoinositide-3 kinase (PI-3K)], [https://en.wikipedia.org/wiki/Epidermal_growth_factor_receptor epidermal growth factor receptor (EGFR)], [https://en.wikipedia.org/wiki/Proto-oncogene_tyrosine-protein_kinase_Src SRC], and [https://en.wikipedia.org/wiki/STAT5 STAT5] phosphorylation. These all result in increased DNA sythesis, [https://en.wikipedia.org/wiki/Cell_growth cell proliferation], and survival. Inhibition of NTSR1 and its downstream signaling represents a target for [https://en.wikipedia.org/wiki/Radiation_therapy radiotherapy]. [[Image: Meclinerant.jpg |100 px|left|thumb|Meclinerant]]NTSR1 can be inhibited by agonist [https://en.wikipedia.org/wiki/Meclinertant meclinertant] which has shown evidence for the inhibition of proliferation and prosurvival of cancer cells. Treatment of radiation and meclinerant has shown to provide selective treatment of cancer cells over normal cells, indicating the need for clinical trials of this approach. <ref name="Valerie">PMID:21903767</ref> <ref name="Kisfalvi">PMID:19679549</ref>

</StructureSection>
== References ==
<references/>

Sandbox reserved 1169

2016-04-12T12:29:50Z

Andrew Koelper:

==Neurotensin Receptor (''Rattus norvegicus'')==
<StructureSection load='4GRV2.pdb' size='340' frame= 'true' align='right' caption='Neurotensin G-Protein Coupled Receptor (PDB Codes [http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV] and [http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE])' <scene='72/727765/Overall_structure/2'/>
== Introduction ==
The neurotensin receptor (NTSR1) belongs to the superfamily of proteins known as [http://proteopedia.org/wiki/index.php/G_protein-coupled_receptor G protein-coupled receptors] (GPCRs) and responds to the 13 amino acid hormone [https://en.wikipedia.org/wiki/Neurotensin neurotensin (NTS)]. There are currently around 800 G protein-coupled receptors that have been identified and are thought to be responsible for roughly 80% of [https://en.wikipedia.org/wiki/Signal_transduction signal transduction] across the cell membrane.<ref name="Millar">PMID:20019124</ref> These receptors are involved in a vast array of physiological processes within the body that range from interactions with [https://en.wikipedia.org/wiki/Dopamine dopamine] to effects on secretion of bile in the intestines.<ref name="Gui">PMID:11208724</ref> <ref name="Binder">PMID:1173461</ref> Due to the vast array of functions that these proteins serve and their high abundance within the body, these proteins have become a major site of drug targets in medicine making a deeper, more in depth understanding of these proteins very important. <ref name="Fang">PMID:23573662</ref> There are currently no NTRS1 structures of the inactive state, so there is no way to determine the [https://en.wikipedia.org/wiki/Conformational_change conformational change] of the binding pocket caused by the binding of NTS. <ref name="White">PMID:23051748</ref>
== Neurotensin ==
[https://en.wikipedia.org/wiki/Neurotensin Neurotensin (NTS)] is a 13-amino acid peptide originally isolated from [https://en.wikipedia.org/w/index.php?title=Bovinae&redirect=no bovine] [https://en.wikipedia.org/wiki/Hypothalamus hypothalamus]. It fulfills the role of both a [https://en.wikipedia.org/wiki/Neurotransmitter neurotransmitter] and a [https://en.wikipedia.org/wiki/Neuromodulation neuromodulator] in the nervous system and a [https://en.wikipedia.org/wiki/Hormone hormone] in the periphery. NTS is a neuromodulator of dopamine transmission and of anterior [https://en.wikipedia.org/wiki/Pituitary_gland pituitary] hormone secretion. It is also a [https://en.wikipedia.org/w/index.php?title=Paracrine_signalling&redirect=no paracrine] and [https://en.wikipedia.org/wiki/Endocrine_system endocrine] modulator in the periphery of the digestive tract and cardiovascular system. Finally, NTS serves as a [https://en.wikipedia.org/wiki/Growth_factor growth factor] for many normal and cancerous cell types.<ref name="Vincent">PMID:10390649</ref>

Only the C-terminal tail of NTS, amino acids 8-13, were resolved in the <scene name='72/721539/Nts8_13/1'>crystal structure</scene>.(PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]
== Structure ==
=== Overall Structure ===
[[Image:Nuerotensin membrane.jpg |100 px|left|thumb|Neurotensin Incorporation in Membrane ]]
Like other G protein-coupled receptors, the neurotensin receptor is composed of 3 distinct regions. An extracellular binding site where neurotensin binds and causes a conformational change of the protein, a region containing <scene name='72/727765/Overall_structure/1'>7 transmembrane alpha helices</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] that transduce the signal from the extracellular side of the cell membrane to the intracellular side, and an intracellular region that, when activated by a conformational change in the protein, activates a [https://en.wikipedia.org/wiki/G_protein G protein] associated with this receptor. There are currently no crystal structures of the inactive form of the neurotensin receptor available. Without a representation of the inactive form, the conformational changes caused by agonist binding are still not completely known.
=== Neurotensin Binding Site ===
Binding of NTS to the binding site is enriched by <scene name='72/721539/Binding_pocket_surface/3'>charge complementarity</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]between the positive NTS arginine side chains and the [https://en.wikipedia.org/wiki/Electronegativity electronegative] pocket. In addition, the C-terminus forms a <scene name='72/721539/Binding_site_charges/2'>salt bridge</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] with R328. Only three out of eight [https://en.wikipedia.org/wiki/Hydrogen_bond hydrogen bonds] are made between the side chains of NTS and the receptor. Most of the interactions are [https://en.wikipedia.org/wiki/Van_der_Waals_force van der Waals] interactions. The binding pocket is partially capped by a [https://en.wikipedia.org/wiki/Beta_hairpin β-hairpin loop] at the proximal end of the receptor protein's N-terminus.<ref name="White"/>
=== Hydrophobic Stacking ===
A major player in the transduction of the extracellular signal to the intracellular G protein is the <scene name='72/727765/Hydrogen_bonding_network/1'>hydrogen bonding network</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]that links the bound hormone with the [https://en.wikipedia.org/wiki/Hydrophobe hydrophobic] core of the neurotensin receptor. The carboxylate of L13 forms a hydrogen bond network with R327, R328, and Y324. The Y324, in turn, is brought into an orientation to make the formation of a <scene name='72/727765/Hydrophobic_stacking_4xee/1'>hydrophobic stacking</scene> (PDB Code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE]) network between F358, W321, A157, and F317 possible.<ref name="Krumm">PMID:23051748</ref> The conformational changes caused by this stacking allows for the signal to be moved from the extracellular binding site through the transmembrane helices of the receptor to the intracellular region activating the G protein.
== Sodium Binding Pocket ==
Conserved across all class A GPCRs, a <scene name='72/727765/Gw5_na_pocket_final/2'>sodium ion-binding pocket</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] is seen in the middle of TM2 helix. The ion is coordinated with a highly conserved D2.50 and four other contacts with oxygen atoms. Some of these oxygen atoms are sourced from water molecules. In order for G-protein activation, a <scene name='72/721539/4xee_na_binding_pocket/1'>hydrogen bond network</scene> (PDB Code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE]) with T3.39, S7.46 ,N7.49 of the NPxxY [https://en.wikipedia.org/wiki/Structural_motif motif], prevents the coordination of a Na+. <ref name="Krumm"/><ref name="Katritch">PMID:24767681</ref>
=== Allosteric Effects ===
Sodium ions are a negative [https://en.wikipedia.org/wiki/Allosteric_regulation allosteric] inhibitor to the binding of the neurotensin [https://en.wikipedia.org/wiki/Agonist agonist] to the binding site on the neurotensin receptor. D113 of the highly conserved D/RY motif and N365 of the highly conserved NPxxY motif form a substantial hydrogen bonding network with T156 and S362.<ref name="Krumm"/> This hydrogen bonding network prevents the incorporation of the sodium ion by collapsing upon itself and therefor filling the sodium binding pocket. W321 also works to inhibit the incorporation of the sodium ion by capping off the sodium binding pocket to not allow sodium to enter from the top. W321 uses van der Walls interactions with other amino acids in the binding pocket to place it in the conformation necessary to complete this task.
==Clinical Relevance==
NTSR1 is commonly expressed in various invasive [https://en.wikipedia.org/wiki/Cancer cancer] cell lines. It is prevalent in the [https://en.wikipedia.org/wiki/Colorectal_cancer colon cancer] [https://en.wikipedia.org/wiki/Adenocarcinoma adenocarcinoma], but is not found in adult colon cell types. NTSR1 is also found in aggressive [https://en.wikipedia.org/wiki/Prostate_cancer prostate cancer] cells, but not [https://en.wikipedia.org/wiki/Epithelium epithelial] prostate cells. In prostate cancer cells, binding of the NTS results in [https://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase mitogen-activated protein kinase (PKB)], [https://en.wikipedia.org/wiki/Phosphoinositide_3-kinase phosphoinositide-3 kinase (PI-3K)], [https://en.wikipedia.org/wiki/Epidermal_growth_factor_receptor epidermal growth factor receptor (EGFR)], [https://en.wikipedia.org/wiki/Proto-oncogene_tyrosine-protein_kinase_Src SRC], and [https://en.wikipedia.org/wiki/STAT5 STAT5] phosphorylation. These all result in increased DNA sythesis, [https://en.wikipedia.org/wiki/Cell_growth cell proliferation], and survival. Inhibition of NTSR1 and its downstream signaling represents a target for [https://en.wikipedia.org/wiki/Radiation_therapy radiotherapy]. [[Image: Meclinerant.jpg |100 px|left|thumb|Meclinerant]]NTSR1 can be inhibited by agonist [https://en.wikipedia.org/wiki/Meclinertant meclinertant] which has shown evidence for the inhibition of proliferation and prosurvival of cancer cells. Treatment of radiation and meclinerant has shown to provide selective treatment of cancer cells over normal cells, indicating the need for clinical trials of this approach. <ref name="Valerie">PMID:21903767</ref> <ref name="Kisfalvi">PMID:19679549</ref>

</StructureSection>
== References ==
<references/>

Sandbox reserved 1169

2016-04-12T12:28:12Z

Andrew Koelper:

==Neurotensin Receptor (''Rattus norvegicus'')==
<StructureSection load='4GRV2.pdb' size='340' frame= 'true' align='right' caption='Neurotensin G-Protein Coupled Receptor (PDB Codes [http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV] and [http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE])' <scene='72/727765/Overall_structure/2'/></scene>
== Introduction ==
The neurotensin receptor (NTSR1) belongs to the superfamily of proteins known as [http://proteopedia.org/wiki/index.php/G_protein-coupled_receptor G protein-coupled receptors] (GPCRs) and responds to the 13 amino acid hormone [https://en.wikipedia.org/wiki/Neurotensin neurotensin (NTS)]. There are currently around 800 G protein-coupled receptors that have been identified and are thought to be responsible for roughly 80% of [https://en.wikipedia.org/wiki/Signal_transduction signal transduction] across the cell membrane.<ref name="Millar">PMID:20019124</ref> These receptors are involved in a vast array of physiological processes within the body that range from interactions with [https://en.wikipedia.org/wiki/Dopamine dopamine] to effects on secretion of bile in the intestines.<ref name="Gui">PMID:11208724</ref> <ref name="Binder">PMID:1173461</ref> Due to the vast array of functions that these proteins serve and their high abundance within the body, these proteins have become a major site of drug targets in medicine making a deeper, more in depth understanding of these proteins very important. <ref name="Fang">PMID:23573662</ref> There are currently no NTRS1 structures of the inactive state, so there is no way to determine the [https://en.wikipedia.org/wiki/Conformational_change conformational change] of the binding pocket caused by the binding of NTS. <ref name="White">PMID:23051748</ref>
== Neurotensin ==
[https://en.wikipedia.org/wiki/Neurotensin Neurotensin (NTS)] is a 13-amino acid peptide originally isolated from [https://en.wikipedia.org/w/index.php?title=Bovinae&redirect=no bovine] [https://en.wikipedia.org/wiki/Hypothalamus hypothalamus]. It fulfills the role of both a [https://en.wikipedia.org/wiki/Neurotransmitter neurotransmitter] and a [https://en.wikipedia.org/wiki/Neuromodulation neuromodulator] in the nervous system and a [https://en.wikipedia.org/wiki/Hormone hormone] in the periphery. NTS is a neuromodulator of dopamine transmission and of anterior [https://en.wikipedia.org/wiki/Pituitary_gland pituitary] hormone secretion. It is also a [https://en.wikipedia.org/w/index.php?title=Paracrine_signalling&redirect=no paracrine] and [https://en.wikipedia.org/wiki/Endocrine_system endocrine] modulator in the periphery of the digestive tract and cardiovascular system. Finally, NTS serves as a [https://en.wikipedia.org/wiki/Growth_factor growth factor] for many normal and cancerous cell types.<ref name="Vincent">PMID:10390649</ref>

Only the C-terminal tail of NTS, amino acids 8-13, were resolved in the <scene name='72/721539/Nts8_13/1'>crystal structure</scene>.(PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]
== Structure ==
=== Overall Structure ===
[[Image:Nuerotensin membrane.jpg |100 px|left|thumb|Neurotensin Incorporation in Membrane ]]
Like other G protein-coupled receptors, the neurotensin receptor is composed of 3 distinct regions. An extracellular binding site where neurotensin binds and causes a conformational change of the protein, a region containing <scene name='72/727765/Overall_structure/1'>7 transmembrane alpha helices</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] that transduce the signal from the extracellular side of the cell membrane to the intracellular side, and an intracellular region that, when activated by a conformational change in the protein, activates a [https://en.wikipedia.org/wiki/G_protein G protein] associated with this receptor. There are currently no crystal structures of the inactive form of the neurotensin receptor available. Without a representation of the inactive form, the conformational changes caused by agonist binding are still not completely known.
=== Neurotensin Binding Site ===
Binding of NTS to the binding site is enriched by <scene name='72/721539/Binding_pocket_surface/3'>charge complementarity</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]between the positive NTS arginine side chains and the [https://en.wikipedia.org/wiki/Electronegativity electronegative] pocket. In addition, the C-terminus forms a <scene name='72/721539/Binding_site_charges/2'>salt bridge</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] with R328. Only three out of eight [https://en.wikipedia.org/wiki/Hydrogen_bond hydrogen bonds] are made between the side chains of NTS and the receptor. Most of the interactions are [https://en.wikipedia.org/wiki/Van_der_Waals_force van der Waals] interactions. The binding pocket is partially capped by a [https://en.wikipedia.org/wiki/Beta_hairpin β-hairpin loop] at the proximal end of the receptor protein's N-terminus.<ref name="White"/>
=== Hydrophobic Stacking ===
A major player in the transduction of the extracellular signal to the intracellular G protein is the <scene name='72/727765/Hydrogen_bonding_network/1'>hydrogen bonding network</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]that links the bound hormone with the [https://en.wikipedia.org/wiki/Hydrophobe hydrophobic] core of the neurotensin receptor. The carboxylate of L13 forms a hydrogen bond network with R327, R328, and Y324. The Y324, in turn, is brought into an orientation to make the formation of a <scene name='72/727765/Hydrophobic_stacking_4xee/1'>hydrophobic stacking</scene> (PDB Code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE]) network between F358, W321, A157, and F317 possible.<ref name="Krumm">PMID:23051748</ref> The conformational changes caused by this stacking allows for the signal to be moved from the extracellular binding site through the transmembrane helices of the receptor to the intracellular region activating the G protein.
== Sodium Binding Pocket ==
Conserved across all class A GPCRs, a <scene name='72/727765/Gw5_na_pocket_final/2'>sodium ion-binding pocket</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] is seen in the middle of TM2 helix. The ion is coordinated with a highly conserved D2.50 and four other contacts with oxygen atoms. Some of these oxygen atoms are sourced from water molecules. In order for G-protein activation, a <scene name='72/721539/4xee_na_binding_pocket/1'>hydrogen bond network</scene> (PDB Code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE]) with T3.39, S7.46 ,N7.49 of the NPxxY [https://en.wikipedia.org/wiki/Structural_motif motif], prevents the coordination of a Na+. <ref name="Krumm"/><ref name="Katritch">PMID:24767681</ref>
=== Allosteric Effects ===
Sodium ions are a negative [https://en.wikipedia.org/wiki/Allosteric_regulation allosteric] inhibitor to the binding of the neurotensin [https://en.wikipedia.org/wiki/Agonist agonist] to the binding site on the neurotensin receptor. D113 of the highly conserved D/RY motif and N365 of the highly conserved NPxxY motif form a substantial hydrogen bonding network with T156 and S362.<ref name="Krumm"/> This hydrogen bonding network prevents the incorporation of the sodium ion by collapsing upon itself and therefor filling the sodium binding pocket. W321 also works to inhibit the incorporation of the sodium ion by capping off the sodium binding pocket to not allow sodium to enter from the top. W321 uses van der Walls interactions with other amino acids in the binding pocket to place it in the conformation necessary to complete this task.
==Clinical Relevance==
NTSR1 is commonly expressed in various invasive [https://en.wikipedia.org/wiki/Cancer cancer] cell lines. It is prevalent in the [https://en.wikipedia.org/wiki/Colorectal_cancer colon cancer] [https://en.wikipedia.org/wiki/Adenocarcinoma adenocarcinoma], but is not found in adult colon cell types. NTSR1 is also found in aggressive [https://en.wikipedia.org/wiki/Prostate_cancer prostate cancer] cells, but not [https://en.wikipedia.org/wiki/Epithelium epithelial] prostate cells. In prostate cancer cells, binding of the NTS results in [https://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase mitogen-activated protein kinase (PKB)], [https://en.wikipedia.org/wiki/Phosphoinositide_3-kinase phosphoinositide-3 kinase (PI-3K)], [https://en.wikipedia.org/wiki/Epidermal_growth_factor_receptor epidermal growth factor receptor (EGFR)], [https://en.wikipedia.org/wiki/Proto-oncogene_tyrosine-protein_kinase_Src SRC], and [https://en.wikipedia.org/wiki/STAT5 STAT5] phosphorylation. These all result in increased DNA sythesis, [https://en.wikipedia.org/wiki/Cell_growth cell proliferation], and survival. Inhibition of NTSR1 and its downstream signaling represents a target for [https://en.wikipedia.org/wiki/Radiation_therapy radiotherapy]. [[Image: Meclinerant.jpg |100 px|left|thumb|Meclinerant]]NTSR1 can be inhibited by agonist [https://en.wikipedia.org/wiki/Meclinertant meclinertant] which has shown evidence for the inhibition of proliferation and prosurvival of cancer cells. Treatment of radiation and meclinerant has shown to provide selective treatment of cancer cells over normal cells, indicating the need for clinical trials of this approach. <ref name="Valerie">PMID:21903767</ref> <ref name="Kisfalvi">PMID:19679549</ref>

</StructureSection>
== References ==
<references/>

Sandbox reserved 1169

2016-04-12T12:25:22Z

Andrew Koelper:

==Neurotensin Receptor (''Rattus norvegicus'')==
<StructureSection load='4GRV2.pdb' size='340' frame= 'true' align='right' caption='Neurotensin G-Protein Coupled Receptor (PDB Codes [http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV] and [http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE])' <scene name='72/727765/Overall_structure/2'></scene>
== Introduction ==
The neurotensin receptor (NTSR1) belongs to the superfamily of proteins known as [http://proteopedia.org/wiki/index.php/G_protein-coupled_receptor G protein-coupled receptors] (GPCRs) and responds to the 13 amino acid hormone [https://en.wikipedia.org/wiki/Neurotensin neurotensin (NTS)]. There are currently around 800 G protein-coupled receptors that have been identified and are thought to be responsible for roughly 80% of [https://en.wikipedia.org/wiki/Signal_transduction signal transduction] across the cell membrane.<ref name="Millar">PMID:20019124</ref> These receptors are involved in a vast array of physiological processes within the body that range from interactions with [https://en.wikipedia.org/wiki/Dopamine dopamine] to effects on secretion of bile in the intestines.<ref name="Gui">PMID:11208724</ref> <ref name="Binder">PMID:1173461</ref> Due to the vast array of functions that these proteins serve and their high abundance within the body, these proteins have become a major site of drug targets in medicine making a deeper, more in depth understanding of these proteins very important. <ref name="Fang">PMID:23573662</ref> There are currently no NTRS1 structures of the inactive state, so there is no way to determine the [https://en.wikipedia.org/wiki/Conformational_change conformational change] of the binding pocket caused by the binding of NTS. <ref name="White">PMID:23051748</ref>
== Neurotensin ==
[https://en.wikipedia.org/wiki/Neurotensin Neurotensin (NTS)] is a 13-amino acid peptide originally isolated from [https://en.wikipedia.org/w/index.php?title=Bovinae&redirect=no bovine] [https://en.wikipedia.org/wiki/Hypothalamus hypothalamus]. It fulfills the role of both a [https://en.wikipedia.org/wiki/Neurotransmitter neurotransmitter] and a [https://en.wikipedia.org/wiki/Neuromodulation neuromodulator] in the nervous system and a [https://en.wikipedia.org/wiki/Hormone hormone] in the periphery. NTS is a neuromodulator of dopamine transmission and of anterior [https://en.wikipedia.org/wiki/Pituitary_gland pituitary] hormone secretion. It is also a [https://en.wikipedia.org/w/index.php?title=Paracrine_signalling&redirect=no paracrine] and [https://en.wikipedia.org/wiki/Endocrine_system endocrine] modulator in the periphery of the digestive tract and cardiovascular system. Finally, NTS serves as a [https://en.wikipedia.org/wiki/Growth_factor growth factor] for many normal and cancerous cell types.<ref name="Vincent">PMID:10390649</ref>

Only the C-terminal tail of NTS, amino acids 8-13, were resolved in the <scene name='72/721539/Nts8_13/1'>crystal structure</scene>.(PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]
== Structure ==
=== Overall Structure ===
[[Image:Nuerotensin membrane.jpg |100 px|left|thumb|Neurotensin Incorporation in Membrane ]]
Like other G protein-coupled receptors, the neurotensin receptor is composed of 3 distinct regions. An extracellular binding site where neurotensin binds and causes a conformational change of the protein, a region containing <scene name='72/727765/Overall_structure/1'>7 transmembrane alpha helices</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] that transduce the signal from the extracellular side of the cell membrane to the intracellular side, and an intracellular region that, when activated by a conformational change in the protein, activates a [https://en.wikipedia.org/wiki/G_protein G protein] associated with this receptor. There are currently no crystal structures of the inactive form of the neurotensin receptor available. Without a representation of the inactive form, the conformational changes caused by agonist binding are still not completely known.
=== Neurotensin Binding Site ===
Binding of NTS to the binding site is enriched by <scene name='72/721539/Binding_pocket_surface/3'>charge complementarity</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]between the positive NTS arginine side chains and the [https://en.wikipedia.org/wiki/Electronegativity electronegative] pocket. In addition, the C-terminus forms a <scene name='72/721539/Binding_site_charges/2'>salt bridge</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] with R328. Only three out of eight [https://en.wikipedia.org/wiki/Hydrogen_bond hydrogen bonds] are made between the side chains of NTS and the receptor. Most of the interactions are [https://en.wikipedia.org/wiki/Van_der_Waals_force van der Waals] interactions. The binding pocket is partially capped by a [https://en.wikipedia.org/wiki/Beta_hairpin β-hairpin loop] at the proximal end of the receptor protein's N-terminus.<ref name="White"/>
=== Hydrophobic Stacking ===
A major player in the transduction of the extracellular signal to the intracellular G protein is the <scene name='72/727765/Hydrogen_bonding_network/1'>hydrogen bonding network</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]that links the bound hormone with the [https://en.wikipedia.org/wiki/Hydrophobe hydrophobic] core of the neurotensin receptor. The carboxylate of L13 forms a hydrogen bond network with R327, R328, and Y324. The Y324, in turn, is brought into an orientation to make the formation of a <scene name='72/727765/Hydrophobic_stacking_4xee/1'>hydrophobic stacking</scene> (PDB Code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE]) network between F358, W321, A157, and F317 possible.<ref name="Krumm">PMID:23051748</ref> The conformational changes caused by this stacking allows for the signal to be moved from the extracellular binding site through the transmembrane helices of the receptor to the intracellular region activating the G protein.
== Sodium Binding Pocket ==
Conserved across all class A GPCRs, a <scene name='72/727765/Gw5_na_pocket_final/2'>sodium ion-binding pocket</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] is seen in the middle of TM2 helix. The ion is coordinated with a highly conserved D2.50 and four other contacts with oxygen atoms. Some of these oxygen atoms are sourced from water molecules. In order for G-protein activation, a <scene name='72/721539/4xee_na_binding_pocket/1'>hydrogen bond network</scene> (PDB Code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE]) with T3.39, S7.46 ,N7.49 of the NPxxY [https://en.wikipedia.org/wiki/Structural_motif motif], prevents the coordination of a Na+. <ref name="Krumm"/><ref name="Katritch">PMID:24767681</ref>
=== Allosteric Effects ===
Sodium ions are a negative [https://en.wikipedia.org/wiki/Allosteric_regulation allosteric] inhibitor to the binding of the neurotensin [https://en.wikipedia.org/wiki/Agonist agonist] to the binding site on the neurotensin receptor. D113 of the highly conserved D/RY motif and N365 of the highly conserved NPxxY motif form a substantial hydrogen bonding network with T156 and S362.<ref name="Krumm"/> This hydrogen bonding network prevents the incorporation of the sodium ion by collapsing upon itself and therefor filling the sodium binding pocket. W321 also works to inhibit the incorporation of the sodium ion by capping off the sodium binding pocket to not allow sodium to enter from the top. W321 uses van der Walls interactions with other amino acids in the binding pocket to place it in the conformation necessary to complete this task.
==Clinical Relevance==
NTSR1 is commonly expressed in various invasive [https://en.wikipedia.org/wiki/Cancer cancer] cell lines. It is prevalent in the [https://en.wikipedia.org/wiki/Colorectal_cancer colon cancer] [https://en.wikipedia.org/wiki/Adenocarcinoma adenocarcinoma], but is not found in adult colon cell types. NTSR1 is also found in aggressive [https://en.wikipedia.org/wiki/Prostate_cancer prostate cancer] cells, but not [https://en.wikipedia.org/wiki/Epithelium epithelial] prostate cells. In prostate cancer cells, binding of the NTS results in [https://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase mitogen-activated protein kinase (PKB)], [https://en.wikipedia.org/wiki/Phosphoinositide_3-kinase phosphoinositide-3 kinase (PI-3K)], [https://en.wikipedia.org/wiki/Epidermal_growth_factor_receptor epidermal growth factor receptor (EGFR)], [https://en.wikipedia.org/wiki/Proto-oncogene_tyrosine-protein_kinase_Src SRC], and [https://en.wikipedia.org/wiki/STAT5 STAT5] phosphorylation. These all result in increased DNA sythesis, [https://en.wikipedia.org/wiki/Cell_growth cell proliferation], and survival. Inhibition of NTSR1 and its downstream signaling represents a target for [https://en.wikipedia.org/wiki/Radiation_therapy radiotherapy]. [[Image: Meclinerant.jpg |100 px|left|thumb|Meclinerant]]NTSR1 can be inhibited by agonist [https://en.wikipedia.org/wiki/Meclinertant meclinertant] which has shown evidence for the inhibition of proliferation and prosurvival of cancer cells. Treatment of radiation and meclinerant has shown to provide selective treatment of cancer cells over normal cells, indicating the need for clinical trials of this approach. <ref name="Valerie">PMID:21903767</ref> <ref name="Kisfalvi">PMID:19679549</ref>

</StructureSection>
== References ==
<references/>

Sandbox reserved 1169

2016-03-30T03:29:51Z

Andrew Koelper:

==Neurotensin Receptor (''Rattus norvegicus'')==
<StructureSection load='4GRV2.pdb' size='340' frame= 'true' align='right' caption='Neurotensin G-Protein Coupled Receptor (PDB Codes [http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV] and [http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE])' scene='72/721539/Overall_structure/3'/>
== Introduction ==
The neurotensin receptor (NTSR1) belongs to the superfamily of proteins known as [http://proteopedia.org/wiki/index.php/G_protein-coupled_receptor G protein-coupled receptors] (GPCRs) and responds to the 13 amino acid hormone [https://en.wikipedia.org/wiki/Neurotensin neurotensin (NTS)]. There are currently around 800 G protein-coupled receptors that have been identified and are thought to be responsible for roughly 80% of [https://en.wikipedia.org/wiki/Signal_transduction signal transduction] across the cell membrane.<ref name="Millar">PMID:20019124</ref> These receptors are involved in a vast array of physiological processes within the body that range from interactions with [https://en.wikipedia.org/wiki/Dopamine dopamine] to effects on secretion of bile in the intestines.<ref name="Gui">PMID:11208724</ref> <ref name="Binder">PMID:1173461</ref> Due to the vast array of functions that these proteins serve and their high abundance within the body, these proteins have become a major site of drug targets in medicine making a deeper, more in depth understanding of these proteins very important. <ref name="Fang">PMID:23573662</ref> There are currently no NTRS1 structures of the inactive state, so there is no way to determine the [https://en.wikipedia.org/wiki/Conformational_change conformational change] of the binding pocket caused by the binding of NTS. <ref name="White">PMID:23051748</ref>
== Neurotensin ==
[https://en.wikipedia.org/wiki/Neurotensin Neurotensin (NTS)] is a 13-amino acid peptide originally isolated from [https://en.wikipedia.org/w/index.php?title=Bovinae&redirect=no bovine] [https://en.wikipedia.org/wiki/Hypothalamus hypothalamus]. It fulfills the role of both a [https://en.wikipedia.org/wiki/Neurotransmitter neurotransmitter] and a [https://en.wikipedia.org/wiki/Neuromodulation neuromodulator] in the nervous system and a [https://en.wikipedia.org/wiki/Hormone hormone] in the periphery. NTS is a neuromodulator of dopamine transmission and of anterior [https://en.wikipedia.org/wiki/Pituitary_gland pituitary] hormone secretion. It is also a [https://en.wikipedia.org/w/index.php?title=Paracrine_signalling&redirect=no paracrine] and [https://en.wikipedia.org/wiki/Endocrine_system endocrine] modulator in the periphery of the digestive tract and cardiovascular system. Finally, NTS serves as a [https://en.wikipedia.org/wiki/Growth_factor growth factor] for many normal and cancerous cell types.<ref name="Vincent">PMID:10390649</ref>

Only the C-terminal tail of NTS, amino acids 8-13, were resolved in the <scene name='72/721539/Nts8_13/1'>crystal structure</scene>.(PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]
== Structure ==
=== Overall Structure ===
[[Image:Nuerotensin membrane.jpg |100 px|left|thumb|Neurotensin Incorporation in Membrane ]]
Like other G protein-coupled receptors, the neurotensin receptor is composed of 3 distinct regions. An extracellular binding site where neurotensin binds and causes a conformational change of the protein, a region containing <scene name='72/727765/Overall_structure/1'>7 transmembrane alpha helices</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] that transduce the signal from the extracellular side of the cell membrane to the intracellular side, and an intracellular region that, when activated by a conformational change in the protein, activates a [https://en.wikipedia.org/wiki/G_protein G protein] associated with this receptor. There are currently no crystal structures of the inactive form of the neurotensin receptor available. Without a representation of the inactive form, the conformational changes caused by agonist binding are still not completely known.
=== Neurotensin Binding Site ===
Binding of NTS to the binding site is enriched by <scene name='72/721539/Binding_pocket_surface/3'>charge complementarity</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]between the positive NTS arginine side chains and the [https://en.wikipedia.org/wiki/Electronegativity electronegative] pocket. In addition, the C-terminus forms a <scene name='72/721539/Binding_site_charges/2'>salt bridge</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] with R328. Only three out of eight [https://en.wikipedia.org/wiki/Hydrogen_bond hydrogen bonds] are made between the side chains of NTS and the receptor. Most of the interactions are [https://en.wikipedia.org/wiki/Van_der_Waals_force van der Waals] interactions. The binding pocket is partially capped by a [https://en.wikipedia.org/wiki/Beta_hairpin β-hairpin loop] at the proximal end of the receptor protein's N-terminus.<ref name="White"/>
=== Hydrophobic Stacking ===
A major player in the transduction of the extracellular signal to the intracellular G protein is the <scene name='72/727765/Hydrogen_bonding_network/1'>hydrogen bonding network</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]that links the bound hormone with the [https://en.wikipedia.org/wiki/Hydrophobe hydrophobic] core of the neurotensin receptor. The carboxylate of L13 forms a hydrogen bond network with R327, R328, and Y324. The Y324, in turn, is brought into an orientation to make the formation of a <scene name='72/727765/Hydrophobic_stacking_4xee/1'>hydrophobic stacking</scene> (PDB Code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE]) network between F358, W321, A157, and F317 possible.<ref name="Krumm">PMID:23051748</ref> The conformational changes caused by this stacking allows for the signal to be moved from the extracellular binding site through the transmembrane helices of the receptor to the intracellular region activating the G protein.
== Sodium Binding Pocket ==
Conserved across all class A GPCRs, a <scene name='72/727765/Gw5_na_pocket_final/2'>sodium ion-binding pocket</scene> (PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)] is seen in the middle of TM2 helix. The ion is coordinated with a highly conserved D2.50 and four other contacts with oxygen atoms. Some of these oxygen atoms are sourced from water molecules. In order for G-protein activation, a <scene name='72/721539/4xee_na_binding_pocket/1'>hydrogen bond network</scene> (PDB Code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4XEE 4XEE]) with T3.39, S7.46 ,N7.49 of the NPxxY [https://en.wikipedia.org/wiki/Structural_motif motif], prevents the coordination of a Na+. <ref name="Krumm"/><ref name="Katritch">PMID:24767681</ref>
=== Allosteric Effects ===
Sodium ions are a negative [https://en.wikipedia.org/wiki/Allosteric_regulation allosteric] inhibitor to the binding of the neurotensin [https://en.wikipedia.org/wiki/Agonist agonist] to the binding site on the neurotensin receptor. D113 of the highly conserved D/RY motif and N365 of the highly conserved NPxxY motif form a substantial hydrogen bonding network with T156 and S362.<ref name="Krumm"/> This hydrogen bonding network prevents the incorporation of the sodium ion by collapsing upon itself and therefor filling the sodium binding pocket. W321 also works to inhibit the incorporation of the sodium ion by capping off the sodium binding pocket to not allow sodium to enter from the top. W321 uses van der Walls interactions with other amino acids in the binding pocket to place it in the conformation necessary to complete this task.
==Clinical Relevance==
NTSR1 is commonly expressed in various invasive [https://en.wikipedia.org/wiki/Cancer cancer] cell lines. It is prevalent in the [https://en.wikipedia.org/wiki/Colorectal_cancer colon cancer] [https://en.wikipedia.org/wiki/Adenocarcinoma adenocarcinoma], but is not found in adult colon cell types. NTSR1 is also found in aggressive [https://en.wikipedia.org/wiki/Prostate_cancer prostate cancer] cells, but not [https://en.wikipedia.org/wiki/Epithelium epithelial] prostate cells. In prostate cancer cells, binding of the NTS results in [https://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase mitogen-activated protein kinase (PKB)], [https://en.wikipedia.org/wiki/Phosphoinositide_3-kinase phosphoinositide-3 kinase (PI-3K)], [https://en.wikipedia.org/wiki/Epidermal_growth_factor_receptor epidermal growth factor receptor (EGFR)], [https://en.wikipedia.org/wiki/Proto-oncogene_tyrosine-protein_kinase_Src SRC], and [https://en.wikipedia.org/wiki/STAT5 STAT5] phosphorylation. These all result in increased DNA sythesis, [https://en.wikipedia.org/wiki/Cell_growth cell proliferation], and survival. Inhibition of NTSR1 and its downstream signaling represents a target for [https://en.wikipedia.org/wiki/Radiation_therapy radiotherapy]. [[Image: Meclinerant.jpg |100 px|left|thumb|Meclinerant]]NTSR1 can be inhibited by agonist [https://en.wikipedia.org/wiki/Meclinertant meclinertant] which has shown evidence for the inhibition of proliferation and prosurvival of cancer cells. Treatment of radiation and meclinerant has shown to provide selective treatment of cancer cells over normal cells, indicating the need for clinical trials of this approach. <ref name="Valerie">PMID:21903767</ref> <ref name="Kisfalvi">PMID:19679549</ref>

</StructureSection>
== References ==
<references/>

Sandbox reserved 1169

2016-03-30T02:55:40Z

Andrew Koelper:

==Neurotensin Receptor (''Rattus norvegicus'')==
<StructureSection load='4GRV2.pdb' size='340' frame= 'true' align='right' caption='Neurotensin G-Protein Coupled Receptor (PDB Code [http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV]' scene='72/721539/Overall_structure/3'/>
== Introduction ==
The neurotensin receptor (NTSR1) belongs to the superfamily of proteins known as [http://proteopedia.org/wiki/index.php/G_protein-coupled_receptor G protein-coupled receptors] (GPCRs) and responds to the 13 amino acid hormone [https://en.wikipedia.org/wiki/Neurotensin neurotensin (NTS)]. There are currently around 800 G protein-coupled receptors that have been identified and are thought to be responsible for roughly 80% of [https://en.wikipedia.org/wiki/Signal_transduction signal transduction] across the cell membrane.<ref name="Millar">PMID:20019124</ref> These receptors are involved in a vast array of physiological processes within the body that range from interactions with [https://en.wikipedia.org/wiki/Dopamine dopamine] to effects on secretion of bile in the intestines.<ref name="Gui">PMID:11208724</ref> <ref name="Binder">PMID:1173461</ref> Due to the vast array of functions that these proteins serve and their high abundance within the body, these proteins have become a major site of drug targets in medicine making a deeper, more in depth understanding of these proteins very important. <ref name="Fang">PMID:23573662</ref> There are currently no NTRS1 structures of the inactive state, so there is no way to determine the [https://en.wikipedia.org/wiki/Conformational_change conformational change] of the binding pocket caused by the binding of NTS. <ref name="White">PMID:23051748</ref>
== Neurotensin ==
[https://en.wikipedia.org/wiki/Neurotensin Neurotensin (NTS)] is a 13-amino acid peptide originally isolated from [https://en.wikipedia.org/w/index.php?title=Bovinae&redirect=no bovine] [https://en.wikipedia.org/wiki/Hypothalamus hypothalamus]. It fulfills the role of both a [https://en.wikipedia.org/wiki/Neurotransmitter neurotransmitter] and a [https://en.wikipedia.org/wiki/Neuromodulation neuromodulator] in the nervous system and a [https://en.wikipedia.org/wiki/Hormone hormone] in the periphery. NTS is a neuromodulator of dopamine transmission and of anterior [https://en.wikipedia.org/wiki/Pituitary_gland pituitary] hormone secretion. It is also a [https://en.wikipedia.org/w/index.php?title=Paracrine_signalling&redirect=no paracrine] and [https://en.wikipedia.org/wiki/Endocrine_system endocrine] modulator in the periphery of the digestive tract and cardiovascular system. Finally, NTS serves as a [https://en.wikipedia.org/wiki/Growth_factor growth factor] for many normal and cancerous cell types.<ref name="Vincent">PMID:10390649</ref>

Only the C-terminal tail of NTS, amino acids 8-13, were resolved in the <scene name='72/721539/Nts8_13/1'>crystal structure</scene>.(PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]
== Structure ==
=== Overall Structure ===
[[Image:Nuerotensin membrane.jpg |100 px|left|thumb|Neurotensin Incorporation in Membrane ]]
Like other G protein-coupled receptors, the neurotensin receptor is composed of 3 distinct regions. An extracellular binding site where neurotensin binds and causes a conformational change of the protein, a region containing <scene name='72/727765/Overall_structure/1'>7 transmembrane alpha helices</scene> that transduce the signal from the extracellular side of the cell membrane to the intracellular side, and an intracellular region that, when activated by a conformational change in the protein, activates a [https://en.wikipedia.org/wiki/G_protein G protein] associated with this receptor. There are currently no crystal structures of the inactive form of the neurotensin receptor available. Without a representation of the inactive form, the conformational changes caused by agonist binding are still not completely known.
=== Neurotensin Binding Site ===
Binding of NTS to the binding site is enriched by <scene name='72/721539/Binding_pocket_surface/3'>charge complementarity</scene> between the positive NTS arginine side chains and the [https://en.wikipedia.org/wiki/Electronegativity electronegative] pocket. In addition, the C-terminus forms a <scene name='72/721539/Binding_site_charges/2'>salt bridge</scene> with R328. Only three out of eight [https://en.wikipedia.org/wiki/Hydrogen_bond hydrogen bonds] are made between the side chains of NTS and the receptor. Most of the interactions are [https://en.wikipedia.org/wiki/Van_der_Waals_force van der Waals] interactions. The binding pocket is partially capped by a [https://en.wikipedia.org/wiki/Beta_hairpin β-hairpin loop] at the proximal end of the receptor protein's N-terminus.<ref name="White"/>
=== Hydrophobic Stacking ===
A major player in the transduction of the extracellular signal to the intracellular G protein is the <scene name='72/727765/Hydrogen_bonding_network/1'>hydrogen bonding network</scene> that links the bound hormone with the [https://en.wikipedia.org/wiki/Hydrophobe hydrophobic] core of the neurotensin receptor. The carboxylate of L13 forms a hydrogen bond network with R327, R328, and Y324. The Y324, in turn, is brought into an orientation to make the formation of a <scene name='72/727765/Hydrophobic_stacking_4xee/1'>hydrophobic stacking</scene> network between F358, W321, A157, and F317 possible.<ref name="Krumm">PMID:23051748</ref> The conformational changes caused by this stacking allows for the signal to be moved from the extracellular binding site through the transmembrane helices of the receptor to the intracellular region activating the G protein.
== Sodium Binding Pocket ==
Conserved across all class A GPCRs, a <scene name='72/727765/Gw5_na_pocket_final/3'>sodium ion-binding pocket</scene> is seen in the middle of TM2 helix. The ion is coordinated with a highly conserved D2.50 and four other contacts with oxygen atoms. Some of these oxygen atoms are sourced from water molecules. In order for G-protein activation, a <scene name='72/721539/4xee_na_binding_pocket/1'>hydrogen bond network</scene> with T3.39, S7.46 ,N7.49 of the NPxxY [https://en.wikipedia.org/wiki/Structural_motif motif], prevents the coordination of a Na+. <ref name="Krumm"/><ref name="Katritch">PMID:24767681</ref>
=== Allosteric Effects ===
Sodium ions are a negative [https://en.wikipedia.org/wiki/Allosteric_regulation allosteric] inhibitor to the binding of the neurotensin [https://en.wikipedia.org/wiki/Agonist agonist] to the binding site on the neurotensin receptor. D113 of the highly conserved D/RY motif and N365 of the highly conserved NPxxY motif form a substantial hydrogen bonding network with T156 and S362.<ref name="Krumm"/> This hydrogen bonding network prevents the incorporation of the sodium ion by collapsing upon itself and therefor filling the sodium binding pocket. W321 also works to inhibit the incorporation of the sodium ion by capping off the sodium binding pocket to not allow sodium to enter from the top. W321 uses van der Walls interactions with other amino acids in the binding pocket to place it in the conformation necessary to complete this task.
==Clinical Relevance==
NTSR1 is commonly expressed in various invasive [https://en.wikipedia.org/wiki/Cancer cancer] cell lines. It is prevalent in the [https://en.wikipedia.org/wiki/Colorectal_cancer colon cancer] [https://en.wikipedia.org/wiki/Adenocarcinoma adenocarcinoma], but is not found in adult colon cell types. NTSR1 is also found in aggressive [https://en.wikipedia.org/wiki/Prostate_cancer prostate cancer] cells, but not [https://en.wikipedia.org/wiki/Epithelium epithelial] prostate cells. In prostate cancer cells, binding of the NTS results in [https://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase mitogen-activated protein kinase (PKB)], [https://en.wikipedia.org/wiki/Phosphoinositide_3-kinase phosphoinositide-3 kinase (PI-3K)], [https://en.wikipedia.org/wiki/Epidermal_growth_factor_receptor epidermal growth factor receptor (EGFR)], [https://en.wikipedia.org/wiki/Proto-oncogene_tyrosine-protein_kinase_Src SRC], and [https://en.wikipedia.org/wiki/STAT5 STAT5] phosphorylation. These all result in increased DNA sythesis, [https://en.wikipedia.org/wiki/Cell_growth cell proliferation], and survival. Inhibition of NTSR1 and its downstream signaling represents a target for [https://en.wikipedia.org/wiki/Radiation_therapy radiotherapy]. [[Image: Meclinerant.jpg |100 px|left|thumb|Meclinerant]]NTSR1 can be inhibited by agonist [https://en.wikipedia.org/wiki/Meclinertant meclinertant] which has shown evidence for the inhibition of proliferation and prosurvival of cancer cells. Treatment of radiation and meclinerant has shown to provide selective treatment of cancer cells over normal cells, indicating the need for clinical trials of this approach. <ref name="Valerie">PMID:21903767</ref> <ref name="Kisfalvi">PMID:19679549</ref>

</StructureSection>
== References ==
<references/>

Sandbox reserved 1169

2016-03-30T02:53:09Z

Andrew Koelper:

==Neurotensin Receptor (''Rattus norvegicus'')==
<StructureSection load='4GRV2.pdb' size='340' frame= 'true' side='right' caption='Neurotensin G-Protein Coupled Receptor (PDB Code [http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV]' scene='72/721539/Overall_structure/3'/>
== Introduction ==
The neurotensin receptor (NTSR1) belongs to the superfamily of proteins known as [http://proteopedia.org/wiki/index.php/G_protein-coupled_receptor G protein-coupled receptors] (GPCRs) and responds to the 13 amino acid hormone [https://en.wikipedia.org/wiki/Neurotensin neurotensin (NTS)]. There are currently around 800 G protein-coupled receptors that have been identified and are thought to be responsible for roughly 80% of [https://en.wikipedia.org/wiki/Signal_transduction signal transduction] across the cell membrane.<ref name="Millar">PMID:20019124</ref> These receptors are involved in a vast array of physiological processes within the body that range from interactions with [https://en.wikipedia.org/wiki/Dopamine dopamine] to effects on secretion of bile in the intestines.<ref name="Gui">PMID:11208724</ref> <ref name="Binder">PMID:1173461</ref> Due to the vast array of functions that these proteins serve and their high abundance within the body, these proteins have become a major site of drug targets in medicine making a deeper, more in depth understanding of these proteins very important. <ref name="Fang">PMID:23573662</ref> There are currently no NTRS1 structures of the inactive state, so there is no way to determine the [https://en.wikipedia.org/wiki/Conformational_change conformational change] of the binding pocket caused by the binding of NTS. <ref name="White">PMID:23051748</ref>
== Neurotensin ==
[https://en.wikipedia.org/wiki/Neurotensin Neurotensin (NTS)] is a 13-amino acid peptide originally isolated from [https://en.wikipedia.org/w/index.php?title=Bovinae&redirect=no bovine] [https://en.wikipedia.org/wiki/Hypothalamus hypothalamus]. It fulfills the role of both a [https://en.wikipedia.org/wiki/Neurotransmitter neurotransmitter] and a [https://en.wikipedia.org/wiki/Neuromodulation neuromodulator] in the nervous system and a [https://en.wikipedia.org/wiki/Hormone hormone] in the periphery. NTS is a neuromodulator of dopamine transmission and of anterior [https://en.wikipedia.org/wiki/Pituitary_gland pituitary] hormone secretion. It is also a [https://en.wikipedia.org/w/index.php?title=Paracrine_signalling&redirect=no paracrine] and [https://en.wikipedia.org/wiki/Endocrine_system endocrine] modulator in the periphery of the digestive tract and cardiovascular system. Finally, NTS serves as a [https://en.wikipedia.org/wiki/Growth_factor growth factor] for many normal and cancerous cell types.<ref name="Vincent">PMID:10390649</ref>

Only the C-terminal tail of NTS, amino acids 8-13, were resolved in the <scene name='72/721539/Nts8_13/1'>crystal structure</scene>.(PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]
== Structure ==
=== Overall Structure ===
[[Image:Nuerotensin membrane.jpg |100 px|left|thumb|Neurotensin Incorporation in Membrane ]]
Like other G protein-coupled receptors, the neurotensin receptor is composed of 3 distinct regions. An extracellular binding site where neurotensin binds and causes a conformational change of the protein, a region containing <scene name='72/727765/Overall_structure/1'>7 transmembrane alpha helices</scene> that transduce the signal from the extracellular side of the cell membrane to the intracellular side, and an intracellular region that, when activated by a conformational change in the protein, activates a [https://en.wikipedia.org/wiki/G_protein G protein] associated with this receptor. There are currently no crystal structures of the inactive form of the neurotensin receptor available. Without a representation of the inactive form, the conformational changes caused by agonist binding are still not completely known.
=== Neurotensin Binding Site ===
Binding of NTS to the binding site is enriched by <scene name='72/721539/Binding_pocket_surface/3'>charge complementarity</scene> between the positive NTS arginine side chains and the [https://en.wikipedia.org/wiki/Electronegativity electronegative] pocket. In addition, the C-terminus forms a <scene name='72/721539/Binding_site_charges/2'>salt bridge</scene> with R328. Only three out of eight [https://en.wikipedia.org/wiki/Hydrogen_bond hydrogen bonds] are made between the side chains of NTS and the receptor. Most of the interactions are [https://en.wikipedia.org/wiki/Van_der_Waals_force van der Waals] interactions. The binding pocket is partially capped by a [https://en.wikipedia.org/wiki/Beta_hairpin β-hairpin loop] at the proximal end of the receptor protein's N-terminus.<ref name="White"/>
=== Hydrophobic Stacking ===
A major player in the transduction of the extracellular signal to the intracellular G protein is the <scene name='72/727765/Hydrogen_bonding_network/1'>hydrogen bonding network</scene> that links the bound hormone with the [https://en.wikipedia.org/wiki/Hydrophobe hydrophobic] core of the neurotensin receptor. The carboxylate of L13 forms a hydrogen bond network with R327, R328, and Y324. The Y324, in turn, is brought into an orientation to make the formation of a <scene name='72/727765/Hydrophobic_stacking_4xee/1'>hydrophobic stacking</scene> network between F358, W321, A157, and F317 possible.<ref name="Krumm">PMID:23051748</ref> The conformational changes caused by this stacking allows for the signal to be moved from the extracellular binding site through the transmembrane helices of the receptor to the intracellular region activating the G protein.
== Sodium Binding Pocket ==
Conserved across all class A GPCRs, a <scene name='72/727765/Gw5_na_pocket_final/3'>sodium ion-binding pocket</scene> is seen in the middle of TM2 helix. The ion is coordinated with a highly conserved D2.50 and four other contacts with oxygen atoms. Some of these oxygen atoms are sourced from water molecules. In order for G-protein activation, a <scene name='72/721539/4xee_na_binding_pocket/1'>hydrogen bond network</scene> with T3.39, S7.46 ,N7.49 of the NPxxY [https://en.wikipedia.org/wiki/Structural_motif motif], prevents the coordination of a Na+. <ref name="Krumm"/><ref name="Katritch">PMID:24767681</ref>
=== Allosteric Effects ===
Sodium ions are a negative [https://en.wikipedia.org/wiki/Allosteric_regulation allosteric] inhibitor to the binding of the neurotensin [https://en.wikipedia.org/wiki/Agonist agonist] to the binding site on the neurotensin receptor. D113 of the highly conserved D/RY motif and N365 of the highly conserved NPxxY motif form a substantial hydrogen bonding network with T156 and S362.<ref name="Krumm"/> This hydrogen bonding network prevents the incorporation of the sodium ion by collapsing upon itself and therefor filling the sodium binding pocket. W321 also works to inhibit the incorporation of the sodium ion by capping off the sodium binding pocket to not allow sodium to enter from the top. W321 uses van der Walls interactions with other amino acids in the binding pocket to place it in the conformation necessary to complete this task.
==Clinical Relevance==
NTSR1 is commonly expressed in various invasive [https://en.wikipedia.org/wiki/Cancer cancer] cell lines. It is prevalent in the [https://en.wikipedia.org/wiki/Colorectal_cancer colon cancer] [https://en.wikipedia.org/wiki/Adenocarcinoma adenocarcinoma], but is not found in adult colon cell types. NTSR1 is also found in aggressive [https://en.wikipedia.org/wiki/Prostate_cancer prostate cancer] cells, but not [https://en.wikipedia.org/wiki/Epithelium epithelial] prostate cells. In prostate cancer cells, binding of the NTS results in [https://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase mitogen-activated protein kinase (PKB)], [https://en.wikipedia.org/wiki/Phosphoinositide_3-kinase phosphoinositide-3 kinase (PI-3K)], [https://en.wikipedia.org/wiki/Epidermal_growth_factor_receptor epidermal growth factor receptor (EGFR)], [https://en.wikipedia.org/wiki/Proto-oncogene_tyrosine-protein_kinase_Src SRC], and [https://en.wikipedia.org/wiki/STAT5 STAT5] phosphorylation. These all result in increased DNA sythesis, [https://en.wikipedia.org/wiki/Cell_growth cell proliferation], and survival. Inhibition of NTSR1 and its downstream signaling represents a target for [https://en.wikipedia.org/wiki/Radiation_therapy radiotherapy]. [[Image: Meclinerant.jpg |100 px|left|thumb|Meclinerant]]NTSR1 can be inhibited by agonist [https://en.wikipedia.org/wiki/Meclinertant meclinertant] which has shown evidence for the inhibition of proliferation and prosurvival of cancer cells. Treatment of radiation and meclinerant has shown to provide selective treatment of cancer cells over normal cells, indicating the need for clinical trials of this approach. <ref name="Valerie">PMID:21903767</ref> <ref name="Kisfalvi">PMID:19679549</ref>

</StructureSection>
== References ==
<references/>

Sandbox reserved 1169

2016-03-30T02:50:50Z

Andrew Koelper:

==Neurotensin Receptor (''Rattus norvegicus'')==
<StructureSection load='4GRV2.pdb' size='340' frame= 'true' side='right' caption='Neurotensin G-Protein Coupled Receptor (PDB Code [http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV] scene='72/721539/Overall_structure/3'>
== Introduction ==
The neurotensin receptor (NTSR1) belongs to the superfamily of proteins known as [http://proteopedia.org/wiki/index.php/G_protein-coupled_receptor G protein-coupled receptors] (GPCRs) and responds to the 13 amino acid hormone [https://en.wikipedia.org/wiki/Neurotensin neurotensin (NTS)]. There are currently around 800 G protein-coupled receptors that have been identified and are thought to be responsible for roughly 80% of [https://en.wikipedia.org/wiki/Signal_transduction signal transduction] across the cell membrane.<ref name="Millar">PMID:20019124</ref> These receptors are involved in a vast array of physiological processes within the body that range from interactions with [https://en.wikipedia.org/wiki/Dopamine dopamine] to effects on secretion of bile in the intestines.<ref name="Gui">PMID:11208724</ref> <ref name="Binder">PMID:1173461</ref> Due to the vast array of functions that these proteins serve and their high abundance within the body, these proteins have become a major site of drug targets in medicine making a deeper, more in depth understanding of these proteins very important. <ref name="Fang">PMID:23573662</ref> There are currently no NTRS1 structures of the inactive state, so there is no way to determine the [https://en.wikipedia.org/wiki/Conformational_change conformational change] of the binding pocket caused by the binding of NTS. <ref name="White">PMID:23051748</ref>
== Neurotensin ==
[https://en.wikipedia.org/wiki/Neurotensin Neurotensin (NTS)] is a 13-amino acid peptide originally isolated from [https://en.wikipedia.org/w/index.php?title=Bovinae&redirect=no bovine] [https://en.wikipedia.org/wiki/Hypothalamus hypothalamus]. It fulfills the role of both a [https://en.wikipedia.org/wiki/Neurotransmitter neurotransmitter] and a [https://en.wikipedia.org/wiki/Neuromodulation neuromodulator] in the nervous system and a [https://en.wikipedia.org/wiki/Hormone hormone] in the periphery. NTS is a neuromodulator of dopamine transmission and of anterior [https://en.wikipedia.org/wiki/Pituitary_gland pituitary] hormone secretion. It is also a [https://en.wikipedia.org/w/index.php?title=Paracrine_signalling&redirect=no paracrine] and [https://en.wikipedia.org/wiki/Endocrine_system endocrine] modulator in the periphery of the digestive tract and cardiovascular system. Finally, NTS serves as a [https://en.wikipedia.org/wiki/Growth_factor growth factor] for many normal and cancerous cell types.<ref name="Vincent">PMID:10390649</ref>

Only the C-terminal tail of NTS, amino acids 8-13, were resolved in the <scene name='72/721539/Nts8_13/1'>crystal structure</scene>.(PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]
== Structure ==
=== Overall Structure ===
[[Image:Nuerotensin membrane.jpg |100 px|left|thumb|Neurotensin Incorporation in Membrane ]]
Like other G protein-coupled receptors, the neurotensin receptor is composed of 3 distinct regions. An extracellular binding site where neurotensin binds and causes a conformational change of the protein, a region containing <scene name='72/727765/Overall_structure/1'>7 transmembrane alpha helices</scene> that transduce the signal from the extracellular side of the cell membrane to the intracellular side, and an intracellular region that, when activated by a conformational change in the protein, activates a [https://en.wikipedia.org/wiki/G_protein G protein] associated with this receptor. There are currently no crystal structures of the inactive form of the neurotensin receptor available. Without a representation of the inactive form, the conformational changes caused by agonist binding are still not completely known.
=== Neurotensin Binding Site ===
Binding of NTS to the binding site is enriched by <scene name='72/721539/Binding_pocket_surface/3'>charge complementarity</scene> between the positive NTS arginine side chains and the [https://en.wikipedia.org/wiki/Electronegativity electronegative] pocket. In addition, the C-terminus forms a <scene name='72/721539/Binding_site_charges/2'>salt bridge</scene> with R328. Only three out of eight [https://en.wikipedia.org/wiki/Hydrogen_bond hydrogen bonds] are made between the side chains of NTS and the receptor. Most of the interactions are [https://en.wikipedia.org/wiki/Van_der_Waals_force van der Waals] interactions. The binding pocket is partially capped by a [https://en.wikipedia.org/wiki/Beta_hairpin β-hairpin loop] at the proximal end of the receptor protein's N-terminus.<ref name="White"/>
=== Hydrophobic Stacking ===
A major player in the transduction of the extracellular signal to the intracellular G protein is the <scene name='72/727765/Hydrogen_bonding_network/1'>hydrogen bonding network</scene> that links the bound hormone with the [https://en.wikipedia.org/wiki/Hydrophobe hydrophobic] core of the neurotensin receptor. The carboxylate of L13 forms a hydrogen bond network with R327, R328, and Y324. The Y324, in turn, is brought into an orientation to make the formation of a <scene name='72/727765/Hydrophobic_stacking_4xee/1'>hydrophobic stacking</scene> network between F358, W321, A157, and F317 possible.<ref name="Krumm">PMID:23051748</ref> The conformational changes caused by this stacking allows for the signal to be moved from the extracellular binding site through the transmembrane helices of the receptor to the intracellular region activating the G protein.
== Sodium Binding Pocket ==
Conserved across all class A GPCRs, a <scene name='72/727765/Gw5_na_pocket_final/3'>sodium ion-binding pocket</scene> is seen in the middle of TM2 helix. The ion is coordinated with a highly conserved D2.50 and four other contacts with oxygen atoms. Some of these oxygen atoms are sourced from water molecules. In order for G-protein activation, a <scene name='72/721539/4xee_na_binding_pocket/1'>hydrogen bond network</scene> with T3.39, S7.46 ,N7.49 of the NPxxY [https://en.wikipedia.org/wiki/Structural_motif motif], prevents the coordination of a Na+. <ref name="Krumm"/><ref name="Katritch">PMID:24767681</ref>
=== Allosteric Effects ===
Sodium ions are a negative [https://en.wikipedia.org/wiki/Allosteric_regulation allosteric] inhibitor to the binding of the neurotensin [https://en.wikipedia.org/wiki/Agonist agonist] to the binding site on the neurotensin receptor. D113 of the highly conserved D/RY motif and N365 of the highly conserved NPxxY motif form a substantial hydrogen bonding network with T156 and S362.<ref name="Krumm"/> This hydrogen bonding network prevents the incorporation of the sodium ion by collapsing upon itself and therefor filling the sodium binding pocket. W321 also works to inhibit the incorporation of the sodium ion by capping off the sodium binding pocket to not allow sodium to enter from the top. W321 uses van der Walls interactions with other amino acids in the binding pocket to place it in the conformation necessary to complete this task.
==Clinical Relevance==
NTSR1 is commonly expressed in various invasive [https://en.wikipedia.org/wiki/Cancer cancer] cell lines. It is prevalent in the [https://en.wikipedia.org/wiki/Colorectal_cancer colon cancer] [https://en.wikipedia.org/wiki/Adenocarcinoma adenocarcinoma], but is not found in adult colon cell types. NTSR1 is also found in aggressive [https://en.wikipedia.org/wiki/Prostate_cancer prostate cancer] cells, but not [https://en.wikipedia.org/wiki/Epithelium epithelial] prostate cells. In prostate cancer cells, binding of the NTS results in [https://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase mitogen-activated protein kinase (PKB)], [https://en.wikipedia.org/wiki/Phosphoinositide_3-kinase phosphoinositide-3 kinase (PI-3K)], [https://en.wikipedia.org/wiki/Epidermal_growth_factor_receptor epidermal growth factor receptor (EGFR)], [https://en.wikipedia.org/wiki/Proto-oncogene_tyrosine-protein_kinase_Src SRC], and [https://en.wikipedia.org/wiki/STAT5 STAT5] phosphorylation. These all result in increased DNA sythesis, [https://en.wikipedia.org/wiki/Cell_growth cell proliferation], and survival. Inhibition of NTSR1 and its downstream signaling represents a target for [https://en.wikipedia.org/wiki/Radiation_therapy radiotherapy]. [[Image: Meclinerant.jpg |100 px|left|thumb|Meclinerant]]NTSR1 can be inhibited by agonist [https://en.wikipedia.org/wiki/Meclinertant meclinertant] which has shown evidence for the inhibition of proliferation and prosurvival of cancer cells. Treatment of radiation and meclinerant has shown to provide selective treatment of cancer cells over normal cells, indicating the need for clinical trials of this approach. <ref name="Valerie">PMID:21903767</ref> <ref name="Kisfalvi">PMID:19679549</ref>

</StructureSection>
== References ==
<references/>

Sandbox reserved 1169

2016-03-30T02:45:17Z

Andrew Koelper:

==Neurotensin Receptor (''Rattus norvegicus'')==
<StructureSection load='4GRV2.pdb' size='340' side='right' frame= 'true' caption='Neurotensin G-Protein Coupled Receptor (PDB Code [http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV] scene='72/721539/Overall_structure/3'>
== Introduction ==
The neurotensin receptor (NTSR1) belongs to the superfamily of proteins known as [http://proteopedia.org/wiki/index.php/G_protein-coupled_receptor G protein-coupled receptors] (GPCRs) and responds to the 13 amino acid hormone [https://en.wikipedia.org/wiki/Neurotensin neurotensin (NTS)]. There are currently around 800 G protein-coupled receptors that have been identified and are thought to be responsible for roughly 80% of [https://en.wikipedia.org/wiki/Signal_transduction signal transduction] across the cell membrane.<ref name="Millar">PMID:20019124</ref> These receptors are involved in a vast array of physiological processes within the body that range from interactions with [https://en.wikipedia.org/wiki/Dopamine dopamine] to effects on secretion of bile in the intestines.<ref name="Gui">PMID:11208724</ref> <ref name="Binder">PMID:1173461</ref> Due to the vast array of functions that these proteins serve and their high abundance within the body, these proteins have become a major site of drug targets in medicine making a deeper, more in depth understanding of these proteins very important. <ref name="Fang">PMID:23573662</ref> There are currently no NTRS1 structures of the inactive state, so there is no way to determine the [https://en.wikipedia.org/wiki/Conformational_change conformational change] of the binding pocket caused by the binding of NTS. <ref name="White">PMID:23051748</ref>
== Neurotensin ==
[https://en.wikipedia.org/wiki/Neurotensin Neurotensin (NTS)] is a 13-amino acid peptide originally isolated from [https://en.wikipedia.org/w/index.php?title=Bovinae&redirect=no bovine] [https://en.wikipedia.org/wiki/Hypothalamus hypothalamus]. It fulfills the role of both a [https://en.wikipedia.org/wiki/Neurotransmitter neurotransmitter] and a [https://en.wikipedia.org/wiki/Neuromodulation neuromodulator] in the nervous system and a [https://en.wikipedia.org/wiki/Hormone hormone] in the periphery. NTS is a neuromodulator of dopamine transmission and of anterior [https://en.wikipedia.org/wiki/Pituitary_gland pituitary] hormone secretion. It is also a [https://en.wikipedia.org/w/index.php?title=Paracrine_signalling&redirect=no paracrine] and [https://en.wikipedia.org/wiki/Endocrine_system endocrine] modulator in the periphery of the digestive tract and cardiovascular system. Finally, NTS serves as a [https://en.wikipedia.org/wiki/Growth_factor growth factor] for many normal and cancerous cell types.<ref name="Vincent">PMID:10390649</ref>

Only the C-terminal tail of NTS, amino acids 8-13, were resolved in the <scene name='72/721539/Nts8_13/1'>crystal structure</scene>.(PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]
== Structure ==
=== Overall Structure ===
[[Image:Nuerotensin membrane.jpg |100 px|left|thumb|Neurotensin Incorporation in Membrane ]]
Like other G protein-coupled receptors, the neurotensin receptor is composed of 3 distinct regions. An extracellular binding site where neurotensin binds and causes a conformational change of the protein, a region containing <scene name='72/727765/Overall_structure/1'>7 transmembrane alpha helices</scene> that transduce the signal from the extracellular side of the cell membrane to the intracellular side, and an intracellular region that, when activated by a conformational change in the protein, activates a [https://en.wikipedia.org/wiki/G_protein G protein] associated with this receptor. There are currently no crystal structures of the inactive form of the neurotensin receptor available. Without a representation of the inactive form, the conformational changes caused by agonist binding are still not completely known.
=== Neurotensin Binding Site ===
Binding of NTS to the binding site is enriched by <scene name='72/721539/Binding_pocket_surface/3'>charge complementarity</scene> between the positive NTS arginine side chains and the [https://en.wikipedia.org/wiki/Electronegativity electronegative] pocket. In addition, the C-terminus forms a <scene name='72/721539/Binding_site_charges/2'>salt bridge</scene> with R328. Only three out of eight [https://en.wikipedia.org/wiki/Hydrogen_bond hydrogen bonds] are made between the side chains of NTS and the receptor. Most of the interactions are [https://en.wikipedia.org/wiki/Van_der_Waals_force van der Waals] interactions. The binding pocket is partially capped by a [https://en.wikipedia.org/wiki/Beta_hairpin β-hairpin loop] at the proximal end of the receptor protein's N-terminus.<ref name="White"/>
=== Hydrophobic Stacking ===
A major player in the transduction of the extracellular signal to the intracellular G protein is the <scene name='72/727765/Hydrogen_bonding_network/1'>hydrogen bonding network</scene> that links the bound hormone with the [https://en.wikipedia.org/wiki/Hydrophobe hydrophobic] core of the neurotensin receptor. The carboxylate of L13 forms a hydrogen bond network with R327, R328, and Y324. The Y324, in turn, is brought into an orientation to make the formation of a <scene name='72/727765/Hydrophobic_stacking_4xee/1'>hydrophobic stacking</scene> network between F358, W321, A157, and F317 possible.<ref name="Krumm">PMID:23051748</ref> The conformational changes caused by this stacking allows for the signal to be moved from the extracellular binding site through the transmembrane helices of the receptor to the intracellular region activating the G protein.
== Sodium Binding Pocket ==
Conserved across all class A GPCRs, a <scene name='72/727765/Gw5_na_pocket_final/3'>sodium ion-binding pocket</scene> is seen in the middle of TM2 helix. The ion is coordinated with a highly conserved D2.50 and four other contacts with oxygen atoms. Some of these oxygen atoms are sourced from water molecules. In order for G-protein activation, a <scene name='72/721539/4xee_na_binding_pocket/1'>hydrogen bond network</scene> with T3.39, S7.46 ,N7.49 of the NPxxY [https://en.wikipedia.org/wiki/Structural_motif motif], prevents the coordination of a Na+. <ref name="Krumm"/><ref name="Katritch">PMID:24767681</ref>
=== Allosteric Effects ===
Sodium ions are a negative [https://en.wikipedia.org/wiki/Allosteric_regulation allosteric] inhibitor to the binding of the neurotensin [https://en.wikipedia.org/wiki/Agonist agonist] to the binding site on the neurotensin receptor. D113 of the highly conserved D/RY motif and N365 of the highly conserved NPxxY motif form a substantial hydrogen bonding network with T156 and S362.<ref name="Krumm"/> This hydrogen bonding network prevents the incorporation of the sodium ion by collapsing upon itself and therefor filling the sodium binding pocket. W321 also works to inhibit the incorporation of the sodium ion by capping off the sodium binding pocket to not allow sodium to enter from the top. W321 uses van der Walls interactions with other amino acids in the binding pocket to place it in the conformation necessary to complete this task.
==Clinical Relevance==
NTSR1 is commonly expressed in various invasive [https://en.wikipedia.org/wiki/Cancer cancer] cell lines. It is prevalent in the [https://en.wikipedia.org/wiki/Colorectal_cancer colon cancer] [https://en.wikipedia.org/wiki/Adenocarcinoma adenocarcinoma], but is not found in adult colon cell types. NTSR1 is also found in aggressive [https://en.wikipedia.org/wiki/Prostate_cancer prostate cancer] cells, but not [https://en.wikipedia.org/wiki/Epithelium epithelial] prostate cells. In prostate cancer cells, binding of the NTS results in [https://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase mitogen-activated protein kinase (PKB)], [https://en.wikipedia.org/wiki/Phosphoinositide_3-kinase phosphoinositide-3 kinase (PI-3K)], [https://en.wikipedia.org/wiki/Epidermal_growth_factor_receptor epidermal growth factor receptor (EGFR)], [https://en.wikipedia.org/wiki/Proto-oncogene_tyrosine-protein_kinase_Src SRC], and [https://en.wikipedia.org/wiki/STAT5 STAT5] phosphorylation. These all result in increased DNA sythesis, [https://en.wikipedia.org/wiki/Cell_growth cell proliferation], and survival. Inhibition of NTSR1 and its downstream signaling represents a target for [https://en.wikipedia.org/wiki/Radiation_therapy radiotherapy]. [[Image: Meclinerant.jpg |100 px|left|thumb|Meclinerant]]NTSR1 can be inhibited by agonist [https://en.wikipedia.org/wiki/Meclinertant meclinertant] which has shown evidence for the inhibition of proliferation and prosurvival of cancer cells. Treatment of radiation and meclinerant has shown to provide selective treatment of cancer cells over normal cells, indicating the need for clinical trials of this approach. <ref name="Valerie">PMID:21903767</ref> <ref name="Kisfalvi">PMID:19679549</ref>

</StructureSection>
== References ==
<references/>

Sandbox reserved 1169

2016-03-30T02:31:29Z

Andrew Koelper:

==Neurotensin Receptor (''Rattus norvegicus'')==
<StructureSection load='4GRV2.pdb' size='340' side='right' caption='Neurotensin G-Protein Coupled Receptor (PDB Code [http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV] scene='72/721539/Overall_structure/3'>
== Introduction ==
The neurotensin receptor (NTSR1) belongs to the superfamily of proteins known as [http://proteopedia.org/wiki/index.php/G_protein-coupled_receptor G protein-coupled receptors] (GPCRs) and responds to the 13 amino acid hormone [https://en.wikipedia.org/wiki/Neurotensin neurotensin (NTS)]. There are currently around 800 G protein-coupled receptors that have been identified and are thought to be responsible for roughly 80% of [https://en.wikipedia.org/wiki/Signal_transduction signal transduction] across the cell membrane.<ref name="Millar">PMID:20019124</ref> These receptors are involved in a vast array of physiological processes within the body that range from interactions with [https://en.wikipedia.org/wiki/Dopamine dopamine] to effects on secretion of bile in the intestines.<ref name="Gui">PMID:11208724</ref> <ref name="Binder">PMID:1173461</ref> Due to the vast array of functions that these proteins serve and their high abundance within the body, these proteins have become a major site of drug targets in medicine making a deeper, more in depth understanding of these proteins very important. <ref name="Fang">PMID:23573662</ref> There are currently no NTRS1 structures of the inactive state, so there is no way to determine the [https://en.wikipedia.org/wiki/Conformational_change conformational change] of the binding pocket caused by the binding of NTS. <ref name="White">PMID:23051748</ref>
== Neurotensin ==
[https://en.wikipedia.org/wiki/Neurotensin Neurotensin (NTS)] is a 13-amino acid peptide originally isolated from [https://en.wikipedia.org/w/index.php?title=Bovinae&redirect=no bovine] [https://en.wikipedia.org/wiki/Hypothalamus hypothalamus]. It fulfills the role of both a [https://en.wikipedia.org/wiki/Neurotransmitter neurotransmitter] and a [https://en.wikipedia.org/wiki/Neuromodulation neuromodulator] in the nervous system and a [https://en.wikipedia.org/wiki/Hormone hormone] in the periphery. NTS is a neuromodulator of dopamine transmission and of anterior [https://en.wikipedia.org/wiki/Pituitary_gland pituitary] hormone secretion. It is also a [https://en.wikipedia.org/w/index.php?title=Paracrine_signalling&redirect=no paracrine] and [https://en.wikipedia.org/wiki/Endocrine_system endocrine] modulator in the periphery of the digestive tract and cardiovascular system. Finally, NTS serves as a [https://en.wikipedia.org/wiki/Growth_factor growth factor] for many normal and cancerous cell types.<ref name="Vincent">PMID:10390649</ref>

Only the C-terminal tail of NTS, amino acids 8-13, were resolved in the <scene name='72/721539/Nts8_13/1'>crystal structure</scene>.(PDB code:[http://www.rcsb.org/pdb/explore/explore.do?structureId=4GRV 4GRV)]
== Structure ==
=== Overall Structure ===
[[Image:Nuerotensin membrane.jpg |100 px|left|thumb|Neurotensin Incorporation in Membrane ]]
Like other G protein-coupled receptors, the neurotensin receptor is composed of 3 distinct regions. An extracellular binding site where neurotensin binds and causes a conformational change of the protein, a region containing <scene name='72/727765/Overall_structure/1'>7 transmembrane alpha helices</scene> that transduce the signal from the extracellular side of the cell membrane to the intracellular side, and an intracellular region that, when activated by a conformational change in the protein, activates a [https://en.wikipedia.org/wiki/G_protein G protein] associated with this receptor. There are currently no crystal structures of the inactive form of the neurotensin receptor available. Without a representation of the inactive form, the conformational changes caused by agonist binding are still not completely known.
=== Neurotensin Binding Site ===
Binding of NTS to the binding site is enriched by <scene name='72/721539/Binding_pocket_surface/3'>charge complementarity</scene> between the positive NTS arginine side chains and the [https://en.wikipedia.org/wiki/Electronegativity electronegative] pocket. In addition, the C-terminus forms a <scene name='72/721539/Binding_site_charges/2'>salt bridge</scene> with R328. Only three out of eight [https://en.wikipedia.org/wiki/Hydrogen_bond hydrogen bonds] are made between the side chains of NTS and the receptor. Most of the interactions are [https://en.wikipedia.org/wiki/Van_der_Waals_force van der Waals] interactions. The binding pocket is partially capped by a [https://en.wikipedia.org/wiki/Beta_hairpin β-hairpin loop] at the proximal end of the receptor protein's N-terminus.<ref name="White"/>
=== Hydrophobic Stacking ===
A major player in the transduction of the extracellular signal to the intracellular G protein is the <scene name='72/727765/Hydrogen_bonding_network/1'>hydrogen bonding network</scene> that links the bound hormone with the [https://en.wikipedia.org/wiki/Hydrophobe hydrophobic] core of the neurotensin receptor. The carboxylate of L13 forms a hydrogen bond network with R327, R328, and Y324. The Y324, in turn, is brought into an orientation to make the formation of a <scene name='72/727765/Hydrophobic_stacking_4xee/1'>hydrophobic stacking</scene> network between F358, W321, A157, and F317 possible.<ref name="Krumm">PMID:23051748</ref> The conformational changes caused by this stacking allows for the signal to be moved from the extracellular binding site through the transmembrane helices of the receptor to the intracellular region activating the G protein.
== Sodium Binding Pocket ==
Conserved across all class A GPCRs, a <scene name='72/727765/Gw5_na_pocket_final/3'>sodium ion-binding pocket</scene> is seen in the middle of TM2 helix. The ion is coordinated with a highly conserved D2.50 and four other contacts with oxygen atoms. Some of these oxygen atoms are sourced from water molecules. In order for G-protein activation, a <scene name='72/721539/4xee_na_binding_pocket/1'>hydrogen bond network</scene> with T3.39, S7.46 ,N7.49 of the NPxxY [https://en.wikipedia.org/wiki/Structural_motif motif], prevents the coordination of a Na+. <ref name="Krumm"/><ref name="Katritch">PMID:24767681</ref>
=== Allosteric Effects ===
Sodium ions are a negative [https://en.wikipedia.org/wiki/Allosteric_regulation allosteric] inhibitor to the binding of the neurotensin [https://en.wikipedia.org/wiki/Agonist agonist] to the binding site on the neurotensin receptor. D113 of the highly conserved D/RY motif and N365 of the highly conserved NPxxY motif form a substantial hydrogen bonding network with T156 and S362.<ref name="Krumm"/> This hydrogen bonding network prevents the incorporation of the sodium ion by collapsing upon itself and therefor filling the sodium binding pocket. W321 also works to inhibit the incorporation of the sodium ion by capping off the sodium binding pocket to not allow sodium to enter from the top. W321 uses van der Walls interactions with other amino acids in the binding pocket to place it in the conformation necessary to complete this task.
==Clinical Relevance==
NTSR1 is commonly expressed in various invasive [https://en.wikipedia.org/wiki/Cancer cancer] cell lines. It is prevalent in the [https://en.wikipedia.org/wiki/Colorectal_cancer colon cancer] [https://en.wikipedia.org/wiki/Adenocarcinoma adenocarcinoma], but is not found in adult colon cell types. NTSR1 is also found in aggressive [https://en.wikipedia.org/wiki/Prostate_cancer prostate cancer] cells, but not [https://en.wikipedia.org/wiki/Epithelium epithelial] prostate cells. In prostate cancer cells, binding of the NTS results in [https://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase mitogen-activated protein kinase (PKB)], [https://en.wikipedia.org/wiki/Phosphoinositide_3-kinase phosphoinositide-3 kinase (PI-3K)], [https://en.wikipedia.org/wiki/Epidermal_growth_factor_receptor epidermal growth factor receptor (EGFR)], [https://en.wikipedia.org/wiki/Proto-oncogene_tyrosine-protein_kinase_Src SRC], and [https://en.wikipedia.org/wiki/STAT5 STAT5] phosphorylation. These all result in increased DNA sythesis, [https://en.wikipedia.org/wiki/Cell_growth cell proliferation], and survival. Inhibition of NTSR1 and its downstream signaling represents a target for [https://en.wikipedia.org/wiki/Radiation_therapy radiotherapy]. [[Image: Meclinerant.jpg |100 px|left|thumb|Meclinerant]]NTSR1 can be inhibited by agonist [https://en.wikipedia.org/wiki/Meclinertant meclinertant] which has shown evidence for the inhibition of proliferation and prosurvival of cancer cells. Treatment of radiation and meclinerant has shown to provide selective treatment of cancer cells over normal cells, indicating the need for clinical trials of this approach. <ref name="Valerie">PMID:21903767</ref> <ref name="Kisfalvi">PMID:19679549</ref>

</StructureSection>
== References ==
<references/>

Sandbox reserved 1169

2016-03-30T01:32:29Z

Andrew Koelper:

==Neurotensin Receptor (''Rattus norvegicus'')==
<StructureSection load='4GRV2.pdb' size='340' side='right' caption='Neurotensin G-Protein Coupled Receptor' scene='72/721539/Overall_structure/3'>
== Introduction ==
The neurotensin receptor (NTSR1) belongs to the superfamily of proteins known as [http://proteopedia.org/wiki/index.php/G_protein-coupled_receptor G protein-coupled receptors] (GPCRs) and responds to the 13 amino acid hormone [https://en.wikipedia.org/wiki/Neurotensin neurotensin] (NTS). There are currently around 800 G protein-coupled receptors that have been identified and are thought to be responsible for roughly 80% of [https://en.wikipedia.org/wiki/Signal_transduction signal transduction] across the cell membrane.<ref name="Millar">PMID:20019124</ref> These receptors are involved in a vast array of physiological processes within the body that range from interactions with [https://en.wikipedia.org/wiki/Dopamine dopamine] to effects on secretion of bile in the intestines.<ref name="Gui">PMID:11208724</ref> <ref name="Binder">PMID:1173461</ref> Due to the vast array of functions that these proteins serve and their high abundance within the body, these proteins have become a major site of drug targets in medicine making a deeper, more in depth understanding of these proteins very important. <ref name="Fang">PMID:23573662</ref> There are currently no NTRS1 structures of the inactive state, so there is no way to determine the [https://en.wikipedia.org/wiki/Conformational_change conformational change] of the binding pocket caused by the binding of NTS. <ref name="White">PMID:23051748</ref>
== Neurotensin ==
<scene name='72/721539/Nts8_13/1'>Neurotensin(NTS)</scene> is a 13-amino acid peptide originally isolated from [https://en.wikipedia.org/w/index.php?title=Bovinae&redirect=no bovine] [https://en.wikipedia.org/wiki/Hypothalamus hypothalamus]. It fulfills the role of both a [https://en.wikipedia.org/wiki/Neurotransmitter neurotransmitter] and a [https://en.wikipedia.org/wiki/Neuromodulation neuromodulator] in the nervous system and a [https://en.wikipedia.org/wiki/Hormone hormone] in the periphery. NTS is a neuromodulator of dopamine transmission and of anterior [https://en.wikipedia.org/wiki/Pituitary_gland pituitary] hormone secretion. It is also a [https://en.wikipedia.org/w/index.php?title=Paracrine_signalling&redirect=no paracrine] and [https://en.wikipedia.org/wiki/Endocrine_system endocrine] modulator in the periphery of the digestive tract and cardiovascular system. Finally, NTS serves as a [https://en.wikipedia.org/wiki/Growth_factor growth factor] for many normal and cancerous cell types.<ref name="Vincent">PMID:10390649</ref>

Only the C-terminal tail of NTS, amino acids 8-13, were resolved in the crystal structure.
== Structure ==
=== Overall Structure ===
[[Image:Nuerotensin membrane.jpg |100 px|left|thumb|Neurotensin Incorporation in Membrane ]]
Like other G protein-coupled receptors, the neurotensin receptor is composed of 3 distinct regions. An extracellular binding site where neurotensin binds and causes a conformational change of the protein, a region containing <scene name='72/727765/Overall_structure/1'>7 transmembrane alpha helices</scene> that transduce the signal from the extracellular side of the cell membrane to the intracellular side, and an intracellular region that, when activated by a conformational change in the protein, activates a [https://en.wikipedia.org/wiki/G_protein G protein] associated with this receptor. There are currently no crystal structures of the inactive form of the neurotensin receptor available. Without a representation of the inactive form, the conformational changes caused by agonist binding are still not completely known.
=== Neurotensin Binding Site ===
Binding of NTS to the binding site is enriched by <scene name='72/721539/Binding_pocket_surface/3'>charge complementarity</scene> between the positive NTS arginine side chains and the [https://en.wikipedia.org/wiki/Electronegativity electronegative] pocket. In addition, the C-terminus forms a <scene name='72/721539/Binding_site_charges/2'>salt bridge</scene> with R328. Only three out of eight [https://en.wikipedia.org/wiki/Hydrogen_bond hydrogen bonds] are made between the side chains of NTS and the receptor. Most of the interactions are [https://en.wikipedia.org/wiki/Van_der_Waals_force van der Waals] interactions. The binding pocket is partially capped by a [https://en.wikipedia.org/wiki/Beta_hairpin β-hairpin loop] at the proximal end of the receptor protein's N-terminus.<ref name="White"/>
=== Hydrophobic Stacking ===
A major player in the transduction of the extracellular signal to the intracellular G protein is the <scene name='72/727765/Hydrogen_bonding_network/1'>hydrogen bonding network</scene> that links the bound hormone with the [https://en.wikipedia.org/wiki/Hydrophobe hydrophobic] core of the neurotensin receptor. The carboxylate of L13 forms a hydrogen bond network with R327, R328, and Y324. The Y324, in turn, is brought into an orientation to make the formation of a <scene name='72/727765/Hydrophobic_stacking_4xee/1'>hydrophobic stacking</scene> network between F358, W321, A157, and F317 possible.<ref name="Krumm">PMID:23051748</ref> The conformational changes caused by this stacking allows for the signal to be moved from the extracellular binding site through the transmembrane helices of the receptor to the intracellular region activating the G protein.
== Sodium Binding Pocket ==
Conserved across all class A GPCRs, a <scene name='72/727765/Gw5_na_pocket_final/2'>sodium ion-binding pocket</scene> is seen in the middle of TM2 helix. The ion is coordinated with a highly conserved D2.50 and four other contacts with oxygen atoms. Some of these oxygen atoms are sourced from water molecules. In order for G-protein activation, a <scene name='72/721539/4xee_na_binding_pocket/1'>hydrogen bond network</scene> with T3.39, S7.46 ,N7.49 of the NPxxY [https://en.wikipedia.org/wiki/Structural_motif motif], prevents the coordination of a Na+. <ref name="Krumm"/><ref name="Katritch">PMID:24767681</ref>
=== Allosteric Effects ===
Sodium ions are a negative [https://en.wikipedia.org/wiki/Allosteric_regulation allosteric] inhibitor to the binding of the neurotensin [https://en.wikipedia.org/wiki/Agonist agonist] to the binding site on the neurotensin receptor. D113 of the highly conserved D/RY motif and N365 of the highly conserved NPxxY motif form a substantial hydrogen bonding network with T156 and S362.<ref name="Krumm"/> This hydrogen bonding network prevents the incorporation of the sodium ion by collapsing upon itself and therefor filling the sodium binding pocket. W321 also works to inhibit the incorporation of the sodium ion by capping off the sodium binding pocket to not allow sodium to enter from the top. W321 uses van der Walls interactions with other amino acids in the binding pocket to place it in the conformation necessary to complete this task.
==Clinical Relevance==
NTSR1 is commonly expressed in various invasive [https://en.wikipedia.org/wiki/Cancer cancer] cell lines. It is prevalent in the [https://en.wikipedia.org/wiki/Colorectal_cancer colon cancer] [https://en.wikipedia.org/wiki/Adenocarcinoma adenocarcinoma], but is not found in adult colon cell types. NTSR1 is also found in aggressive [https://en.wikipedia.org/wiki/Prostate_cancer prostate cancer] cells, but not [https://en.wikipedia.org/wiki/Epithelium epithelial] prostate cells. In prostate cancer cells, binding of the NTS results in [https://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase mitogen-activated protein kinase (PKB)], [https://en.wikipedia.org/wiki/Phosphoinositide_3-kinase phosphoinositide-3 kinase (PI-3K)], [https://en.wikipedia.org/wiki/Epidermal_growth_factor_receptor epidermal growth factor receptor (EGFR)], [https://en.wikipedia.org/wiki/Proto-oncogene_tyrosine-protein_kinase_Src SRC], and [https://en.wikipedia.org/wiki/STAT5 STAT5] phosphorylation. These all result in increased DNA sythesis, [https://en.wikipedia.org/wiki/Cell_growth cell proliferation], and survival. Inhibition of NTSR1 and its downstream signaling represents a target for radiotherapy. [[Image: Meclinerant.jpg |100 px|left|thumb|Meclinerant]]NTSR1 can be inhibited by agonist meclinertant which has shown evidence for the inhibition of proliferation and prosurvival of cancer cells. Treatment of radiation and meclinerant has shown to provide selective treatment of cancer cells over normal cells, indicating the need for clinical trials of this approach. <ref name="Valerie">PMID:21903767</ref> <ref name="Kisfalvi">PMID:19679549</ref>

</StructureSection>
== References ==
<references/>

Sandbox reserved 1169

2016-03-30T01:31:39Z

Andrew Koelper:

==Neurotensin Receptor (''Rattus norvegicus'')==
<StructureSection load='4GRV2.pdb' size='340' side='right' caption='Neurotensin G-Protein Coupled Receptor' scene='72/721539/Overall_structure/3'>
== Introduction ==
The neurotensin receptor (NTSR1) belongs to the superfamily of proteins known as [http://proteopedia.org/wiki/index.php/G_protein-coupled_receptor G protein-coupled receptors] (GPCRs) and responds to the 13 amino acid hormone [https://en.wikipedia.org/wiki/Neurotensin neurotensin] (NTS). There are currently around 800 G protein-coupled receptors that have been identified and are thought to be responsible for roughly 80% of [https://en.wikipedia.org/wiki/Signal_transduction signal transduction] across the cell membrane.<ref name="Millar">PMID:20019124</ref> These receptors are involved in a vast array of physiological processes within the body that range from interactions with [https://en.wikipedia.org/wiki/Dopamine dopamine] to effects on secretion of bile in the intestines.<ref name="Gui">PMID:11208724</ref> <ref name="Binder">PMID:1173461</ref> Due to the vast array of functions that these proteins serve and their high abundance within the body, these proteins have become a major site of drug targets in medicine making a deeper, more in depth understanding of these proteins very important. <ref name="Fang">PMID:23573662</ref> There are currently no NTRS1 structures of the inactive state, so there is no way to determine the [https://en.wikipedia.org/wiki/Conformational_change conformational change] of the binding pocket caused by the binding of NTS. <ref name="White">PMID:23051748</ref>
== Neurotensin ==
<scene name='72/721539/Nts8_13/1'>Neurotensin(NTS)</scene> is a 13-amino acid peptide originally isolated from [https://en.wikipedia.org/w/index.php?title=Bovinae&redirect=no bovine] [https://en.wikipedia.org/wiki/Hypothalamus hypothalamus]. It fulfills the role of both a [https://en.wikipedia.org/wiki/Neurotransmitter neurotransmitter] and a [https://en.wikipedia.org/wiki/Neuromodulation neuromodulator] in the nervous system and a [https://en.wikipedia.org/wiki/Hormone hormone] in the periphery. NTS is a neuromodulator of dopamine transmission and of anterior [https://en.wikipedia.org/wiki/Pituitary_gland pituitary] hormone secretion. It is also a [https://en.wikipedia.org/w/index.php?title=Paracrine_signalling&redirect=no paracrine] and [https://en.wikipedia.org/wiki/Endocrine_system endocrine] modulator in the periphery of the digestive tract and cardiovascular system. Finally, NTS serves as a [https://en.wikipedia.org/wiki/Growth_factor growth factor] for many normal and cancerous cell types.<ref name="Vincent">PMID:10390649</ref>

Only the C-terminal tail of NTS, amino acids 8-13, were resolved in the crystal structure.
== Structure ==
=== Overall Structure ===
[[Image:Nuerotensin membrane.jpg |100 px|left|thumb|Neurotensin Incorporation in Membrane ]]
Like other G protein-coupled receptors, the neurotensin receptor is composed of 3 distinct regions. An extracellular binding site where neurotensin binds and causes a conformational change of the protein, a region containing <scene name='72/727765/Overall_structure/1'>7 transmembrane alpha helices</scene> that transduce the signal from the extracellular side of the cell membrane to the intracellular side, and an intracellular region that, when activated by a conformational change in the protein, activates a [https://en.wikipedia.org/wiki/G_protein G protein] associated with this receptor. There are currently no crystal structures of the inactive form of the neurotensin receptor available. Without a representation of the inactive form, the conformational changes caused by agonist binding are still not completely known.
=== Neurotensin Binding Site ===
Binding of NTS to the binding site is enriched by <scene name='72/721539/Binding_pocket_surface/3'>charge complementarity</scene> between the positive NTS arginine side chains and the [https://en.wikipedia.org/wiki/Electronegativity electronegative] pocket. In addition, the C-terminus forms a <scene name='72/721539/Binding_site_charges/2'>salt bridge</scene> with R328. Only three out of eight [https://en.wikipedia.org/wiki/Hydrogen_bond hydrogen bonds] are made between the side chains of NTS and the receptor. Most of the interactions are [https://en.wikipedia.org/wiki/Van_der_Waals_force van der Waals] interactions. The binding pocket is partially capped by a [https://en.wikipedia.org/wiki/Beta_hairpin β-hairpin loop] at the proximal end of the receptor protein's N-terminus.<ref name="White"/>
=== Hydrophobic Stacking ===
A major player in the transduction of the extracellular signal to the intracellular G protein is the <scene name='72/727765/Hydrogen_bonding_network/1'>hydrogen bonding network</scene> that links the bound hormone with the [https://en.wikipedia.org/wiki/Hydrophobe hydrophobic] core of the neurotensin receptor. The carboxylate of L13 forms a hydrogen bond network with R327, R328, and Y324. The Y324, in turn, is brought into an orientation to make the formation of a <scene name='72/727765/Hydrophobic_stacking_4xee/1'>hydrophobic stacking</scene> network between F358, W321, A157, and F317 possible.<ref name="Krumm">PMID:23051748</ref> The conformational changes caused by this stacking allows for the signal to be moved from the extracellular binding site through the transmembrane helices of the receptor to the intracellular region activating the G protein.
== Sodium Binding Pocket ==
Conserved across all class A GPCRs, a <scene name='72/727765/Gw5_na_pocket_final/2'>sodium ion-binding pocket</scene> is seen in the middle of TM2 helix. The ion is coordinated with a highly conserved D2.50 and four other contacts with oxygen atoms. Some of these oxygen atoms are sourced from water molecules. In order for G-protein activation, a <scene name='72/721539/4xee_na_binding_pocket/1'>hydrogen bond network</scene> with T3.39, S7.46 ,N7.49 of the NPxxY [https://en.wikipedia.org/wiki/Structural_motif motif], prevents the coordination of a Na+. <ref name="Krumm"/><ref name="Katritch">PMID:24767681</ref>
=== Allosteric Effects ===
Sodium ions are a negative [https://en.wikipedia.org/wiki/Allosteric_regulation allosteric] inhibitor to the binding of the neurotensin [https://en.wikipedia.org/wiki/Agonist agonist] to the binding site on the neurotensin receptor. D113 of the highly conserved D/RY motif and N365 of the highly conserved NPxxY motif form a substantial hydrogen bonding network with T156 and S362.<ref name="Krumm"/> This hydrogen bonding network prevents the incorporation of the sodium ion by collapsing upon itself and therefor filling the sodium binding pocket. W321 also works to inhibit the incorporation of the sodium ion by capping off the sodium binding pocket to not allow sodium to enter from the top. W321 uses van der Walls interactions with other amino acids in the binding pocket to place it in the conformation necessary to complete this task.
==Clinical Relevance==
NTSR1 is commonly expressed in various invasive [https://en.wikipedia.org/wiki/Cancer cancer] cell lines. It is prevalent in the [https://en.wikipedia.org/wiki/Colorectal_cancer colon cancer] [https://en.wikipedia.org/wiki/Adenocarcinoma adenocarcinoma], but is not found in adult colon cell types. NTSR1 is also found in aggressive [https://en.wikipedia.org/wiki/Prostate_cancer prostate cancer] cells, but not [https://en.wikipedia.org/wiki/Epithelium epithelial] prostate cells. In prostate cancer cells, binding of the NTS results in [https://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase mitogen-activated protein kinase (PKB)], [https://en.wikipedia.org/wiki/Phosphoinositide_3-kinase phosphoinositide-3 kinase (PI-3K)], [https://en.wikipedia.org/wiki/Epidermal_growth_factor_receptor epidermal growth factor receptor (EGFR)], [https://en.wikipedia.org/wiki/Proto-oncogene_tyrosine-protein_kinase_Src SRC], and [https://en.wikipedia.org/wiki/STAT5 STAT5] phosphorylation. These all result in increased DNA sythesis, [https://en.wikipedia.org/wiki/Cell_growth cell proliferation], and survival. Inhibition of NTSR1 and its downstream signaling represents a target for radiotherapy. [[Image:Meclinertant.jpg |100 px|left|thumb|Meclinerant]]NTSR1 can be inhibited by agonist meclinertant which has shown evidence for the inhibition of proliferation and prosurvival of cancer cells. Treatment of radiation and meclinerant has shown to provide selective treatment of cancer cells over normal cells, indicating the need for clinical trials of this approach. <ref name="Valerie">PMID:21903767</ref> <ref name="Kisfalvi">PMID:19679549</ref>

</StructureSection>
== References ==
<references/>

File:Meclinerant.jpg

2016-03-30T01:30:25Z

Andrew Koelper:

Sandbox reserved 1169

2016-03-30T01:29:26Z

Andrew Koelper:

==Neurotensin Receptor (''Rattus norvegicus'')==
<StructureSection load='4GRV2.pdb' size='340' side='right' caption='Neurotensin G-Protein Coupled Receptor' scene='72/721539/Overall_structure/3'>
== Introduction ==
The neurotensin receptor (NTSR1) belongs to the superfamily of proteins known as [http://proteopedia.org/wiki/index.php/G_protein-coupled_receptor G protein-coupled receptors] (GPCRs) and responds to the 13 amino acid hormone [https://en.wikipedia.org/wiki/Neurotensin neurotensin] (NTS). There are currently around 800 G protein-coupled receptors that have been identified and are thought to be responsible for roughly 80% of [https://en.wikipedia.org/wiki/Signal_transduction signal transduction] across the cell membrane.<ref name="Millar">PMID:20019124</ref> These receptors are involved in a vast array of physiological processes within the body that range from interactions with [https://en.wikipedia.org/wiki/Dopamine dopamine] to effects on secretion of bile in the intestines.<ref name="Gui">PMID:11208724</ref> <ref name="Binder">PMID:1173461</ref> Due to the vast array of functions that these proteins serve and their high abundance within the body, these proteins have become a major site of drug targets in medicine making a deeper, more in depth understanding of these proteins very important. <ref name="Fang">PMID:23573662</ref> There are currently no NTRS1 structures of the inactive state, so there is no way to determine the [https://en.wikipedia.org/wiki/Conformational_change conformational change] of the binding pocket caused by the binding of NTS. <ref name="White">PMID:23051748</ref>
== Neurotensin ==
<scene name='72/721539/Nts8_13/1'>Neurotensin(NTS)</scene> is a 13-amino acid peptide originally isolated from [https://en.wikipedia.org/w/index.php?title=Bovinae&redirect=no bovine] [https://en.wikipedia.org/wiki/Hypothalamus hypothalamus]. It fulfills the role of both a [https://en.wikipedia.org/wiki/Neurotransmitter neurotransmitter] and a [https://en.wikipedia.org/wiki/Neuromodulation neuromodulator] in the nervous system and a [https://en.wikipedia.org/wiki/Hormone hormone] in the periphery. NTS is a neuromodulator of dopamine transmission and of anterior [https://en.wikipedia.org/wiki/Pituitary_gland pituitary] hormone secretion. It is also a [https://en.wikipedia.org/w/index.php?title=Paracrine_signalling&redirect=no paracrine] and [https://en.wikipedia.org/wiki/Endocrine_system endocrine] modulator in the periphery of the digestive tract and cardiovascular system. Finally, NTS serves as a [https://en.wikipedia.org/wiki/Growth_factor growth factor] for many normal and cancerous cell types.<ref name="Vincent">PMID:10390649</ref>

Only the C-terminal tail of NTS, amino acids 8-13, were resolved in the crystal structure.
== Structure ==
=== Overall Structure ===
[[Image:Nuerotensin membrane.jpg |100 px|left|thumb|Neurotensin Incorporation in Membrane ]]
Like other G protein-coupled receptors, the neurotensin receptor is composed of 3 distinct regions. An extracellular binding site where neurotensin binds and causes a conformational change of the protein, a region containing <scene name='72/727765/Overall_structure/1'>7 transmembrane alpha helices</scene> that transduce the signal from the extracellular side of the cell membrane to the intracellular side, and an intracellular region that, when activated by a conformational change in the protein, activates a [https://en.wikipedia.org/wiki/G_protein G protein] associated with this receptor. There are currently no crystal structures of the inactive form of the neurotensin receptor available. Without a representation of the inactive form, the conformational changes caused by agonist binding are still not completely known.
=== Neurotensin Binding Site ===
Binding of NTS to the binding site is enriched by <scene name='72/721539/Binding_pocket_surface/3'>charge complementarity</scene> between the positive NTS arginine side chains and the [https://en.wikipedia.org/wiki/Electronegativity electronegative] pocket. In addition, the C-terminus forms a <scene name='72/721539/Binding_site_charges/2'>salt bridge</scene> with R328. Only three out of eight [https://en.wikipedia.org/wiki/Hydrogen_bond hydrogen bonds] are made between the side chains of NTS and the receptor. Most of the interactions are [https://en.wikipedia.org/wiki/Van_der_Waals_force van der Waals] interactions. The binding pocket is partially capped by a [https://en.wikipedia.org/wiki/Beta_hairpin β-hairpin loop] at the proximal end of the receptor protein's N-terminus.<ref name="White"/>
=== Hydrophobic Stacking ===
A major player in the transduction of the extracellular signal to the intracellular G protein is the <scene name='72/727765/Hydrogen_bonding_network/1'>hydrogen bonding network</scene> that links the bound hormone with the [https://en.wikipedia.org/wiki/Hydrophobe hydrophobic] core of the neurotensin receptor. The carboxylate of L13 forms a hydrogen bond network with R327, R328, and Y324. The Y324, in turn, is brought into an orientation to make the formation of a <scene name='72/727765/Hydrophobic_stacking_4xee/1'>hydrophobic stacking</scene> network between F358, W321, A157, and F317 possible.<ref name="Krumm">PMID:23051748</ref> The conformational changes caused by this stacking allows for the signal to be moved from the extracellular binding site through the transmembrane helices of the receptor to the intracellular region activating the G protein.
== Sodium Binding Pocket ==
Conserved across all class A GPCRs, a <scene name='72/727765/Gw5_na_pocket_final/2'>sodium ion-binding pocket</scene> is seen in the middle of TM2 helix. The ion is coordinated with a highly conserved D2.50 and four other contacts with oxygen atoms. Some of these oxygen atoms are sourced from water molecules. In order for G-protein activation, a <scene name='72/721539/4xee_na_binding_pocket/1'>hydrogen bond network</scene> with T3.39, S7.46 ,N7.49 of the NPxxY [https://en.wikipedia.org/wiki/Structural_motif motif], prevents the coordination of a Na+. <ref name="Krumm"/><ref name="Katritch">PMID:24767681</ref>
=== Allosteric Effects ===
Sodium ions are a negative [https://en.wikipedia.org/wiki/Allosteric_regulation allosteric] inhibitor to the binding of the neurotensin [https://en.wikipedia.org/wiki/Agonist agonist] to the binding site on the neurotensin receptor. D113 of the highly conserved D/RY motif and N365 of the highly conserved NPxxY motif form a substantial hydrogen bonding network with T156 and S362.<ref name="Krumm"/> This hydrogen bonding network prevents the incorporation of the sodium ion by collapsing upon itself and therefor filling the sodium binding pocket. W321 also works to inhibit the incorporation of the sodium ion by capping off the sodium binding pocket to not allow sodium to enter from the top. W321 uses van der Walls interactions with other amino acids in the binding pocket to place it in the conformation necessary to complete this task.
==Clinical Relevance==
NTSR1 is commonly expressed in various invasive [https://en.wikipedia.org/wiki/Cancer cancer] cell lines. It is prevalent in the [https://en.wikipedia.org/wiki/Colorectal_cancer colon cancer] [https://en.wikipedia.org/wiki/Adenocarcinoma adenocarcinoma], but is not found in adult colon cell types. NTSR1 is also found in aggressive [https://en.wikipedia.org/wiki/Prostate_cancer prostate cancer] cells, but not [https://en.wikipedia.org/wiki/Epithelium epithelial] prostate cells. In prostate cancer cells, binding of the NTS results in [https://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase mitogen-activated protein kinase (PKB)], [https://en.wikipedia.org/wiki/Phosphoinositide_3-kinase phosphoinositide-3 kinase (PI-3K)], [https://en.wikipedia.org/wiki/Epidermal_growth_factor_receptor epidermal growth factor receptor (EGFR)], [https://en.wikipedia.org/wiki/Proto-oncogene_tyrosine-protein_kinase_Src SRC], and [https://en.wikipedia.org/wiki/STAT5 STAT5] phosphorylation. These all result in increased DNA sythesis, [https://en.wikipedia.org/wiki/Cell_growth cell proliferation], and survival. Inhibition of NTSR1 and its downstream signaling represents a target for radiotherapy. [[Image:Nuerotensin membrane.jpg |100 px|left|thumb|Meclinerant]]NTSR1 can be inhibited by agonist meclinertant which has shown evidence for the inhibition of proliferation and prosurvival of cancer cells. Treatment of radiation and meclinerant has shown to provide selective treatment of cancer cells over normal cells, indicating the need for clinical trials of this approach. <ref name="Valerie">PMID:21903767</ref> <ref name="Kisfalvi">PMID:19679549</ref>

</StructureSection>
== References ==
<references/>

Sandbox reserved 1169

2016-03-30T01:03:23Z

Andrew Koelper:

==Neurotensin Receptor (''Rattus norvegicus'')==
<StructureSection load='4GRV2.pdb' size='340' side='right' caption='Neurotensin G-Protein Coupled Receptor' scene='72/721539/Overall_structure/3'>
== Introduction ==
The neurotensin receptor (NTSR1) belongs to the superfamily of proteins known as [http://proteopedia.org/wiki/index.php/G_protein-coupled_receptor G protein-coupled receptors] (GPCRs) and responds to the 13 amino acid hormone [https://en.wikipedia.org/wiki/Neurotensin neurotensin] (NTS). There are currently around 800 G protein-coupled receptors that have been identified and are thought to be responsible for roughly 80% of [https://en.wikipedia.org/wiki/Signal_transduction signal transduction] across the cell membrane.<ref name="Millar">PMID:20019124</ref> These receptors are involved in a vast array of physiological processes within the body that range from interactions with [https://en.wikipedia.org/wiki/Dopamine dopamine] to effects on secretion of bile in the intestines.<ref name="Gui">PMID:11208724</ref> <ref name="Binder">PMID:1173461</ref> Due to the vast array of functions that these proteins serve and their high abundance within the body, these proteins have become a major site of drug targets in medicine making a deeper, more in depth understanding of these proteins very important. <ref name="Fang">PMID:23573662</ref> There are currently no NTRS1 structures of the inactive state, so there is no way to determine the [https://en.wikipedia.org/wiki/Conformational_change conformational change] of the binding pocket caused by the binding of NTS. <ref name="White">PMID:23051748</ref>
== Neurotensin ==
<scene name='72/721539/Nts8_13/1'>Neurotensin(NTS)</scene> is a 13-amino acid peptide originally isolated from [https://en.wikipedia.org/w/index.php?title=Bovinae&redirect=no bovine] [https://en.wikipedia.org/wiki/Hypothalamus hypothalamus]. It fulfills the role of both a [https://en.wikipedia.org/wiki/Neurotransmitter neurotransmitter] and a [https://en.wikipedia.org/wiki/Neuromodulation neuromodulator] in the nervous system and a [https://en.wikipedia.org/wiki/Hormone hormone] in the periphery. NTS is a neuromodulator of dopamine transmission and of anterior [https://en.wikipedia.org/wiki/Pituitary_gland pituitary] hormone secretion. It is also a [https://en.wikipedia.org/w/index.php?title=Paracrine_signalling&redirect=no paracrine] and [https://en.wikipedia.org/wiki/Endocrine_system endocrine] modulator in the periphery of the digestive tract and cardiovascular system. Finally, NTS serves as a [https://en.wikipedia.org/wiki/Growth_factor growth factor] for many normal and cancerous cell types.<ref name="Vincent">PMID:10390649</ref>

Only the C-terminal tail of NTS, amino acids 8-13, were resolved in the crystal structure.
== Structure ==
=== Overall Structure ===
[[Image:Nuerotensin membrane.jpg |100 px|left|thumb|Neurotensin Incorporation in Membrane ]]
Like other G protein-coupled receptors, the neurotensin receptor is composed of 3 distinct regions. An extracellular binding site where neurotensin binds and causes a conformational change of the protein, a region containing <scene name='72/727765/Overall_structure/1'>7 transmembrane alpha helices</scene> that transduce the signal from the extracellular side of the cell membrane to the intracellular side, and an intracellular region that, when activated by a conformational change in the protein, activates a [https://en.wikipedia.org/wiki/G_protein G protein] associated with this receptor. There are currently no crystal structures of the inactive form of the neurotensin receptor available. Without a representation of the inactive form, the conformational changes caused by agonist binding are still not completely known.
=== Neurotensin Binding Site ===
Binding of NTS to the binding site is enriched by <scene name='72/721539/Binding_pocket_surface/3'>charge complementarity</scene> between the positive NTS arginine side chains and the [https://en.wikipedia.org/wiki/Electronegativity electronegative] pocket. In addition, the C-terminus forms a <scene name='72/721539/Binding_site_charges/2'>salt bridge</scene> with R328. Only three out of eight [https://en.wikipedia.org/wiki/Hydrogen_bond hydrogen bonds] are made between the side chains of NTS and the receptor. Most of the interactions are [https://en.wikipedia.org/wiki/Van_der_Waals_force van der Waals] interactions. The binding pocket is partially capped by a [https://en.wikipedia.org/wiki/Beta_hairpin β-hairpin loop] at the proximal end of the receptor protein's N-terminus.<ref name="White"/>
=== Hydrophobic Stacking ===
A major player in the transduction of the extracellular signal to the intracellular G protein is the <scene name='72/727765/Hydrogen_bonding_network/1'>hydrogen bonding network</scene> that links the bound hormone with the [https://en.wikipedia.org/wiki/Hydrophobe hydrophobic] core of the neurotensin receptor. The carboxylate of L13 forms a hydrogen bond network with R327, R328, and Y324. The Y324, in turn, is brought into an orientation to make the formation of a <scene name='72/727765/Hydrophobic_stacking_4xee/1'>hydrophobic stacking</scene> network between F358, W321, A157, and F317 possible.<ref name="Krumm">PMID:23051748</ref> The conformational changes caused by this stacking allows for the signal to be moved from the extracellular binding site through the transmembrane helices of the receptor to the intracellular region activating the G protein.
== Sodium Binding Pocket ==
Conserved across all class A GPCRs, a <scene name='72/727765/Gw5_na_pocket_final/2'>sodium ion-binding pocket</scene> is seen in the middle of TM2 helix. The ion is coordinated with a highly conserved D2.50 and four other contacts with oxygen atoms. Some of these oxygen atoms are sourced from water molecules. In order for G-protein activation, a <scene name='72/721539/4xee_na_binding_pocket/1'>hydrogen bond network</scene> with T3.39, S7.46 ,N7.49 of the NPxxY [https://en.wikipedia.org/wiki/Structural_motif motif], prevents the coordination of a Na+. <ref name="Krumm"/><ref name="Katritch">PMID:24767681</ref>
=== Allosteric Effects ===
Sodium ions are a negative [https://en.wikipedia.org/wiki/Allosteric_regulation allosteric] inhibitor to the binding of the neurotensin [https://en.wikipedia.org/wiki/Agonist agonist] to the binding site on the neurotensin receptor. D113 of the highly conserved D/RY motif and N365 of the highly conserved NPxxY motif form a substantial hydrogen bonding network with T156 and S362.<ref name="Krumm"/> This hydrogen bonding network prevents the incorporation of the sodium ion by collapsing upon itself and therefor filling the sodium binding pocket. W321 also works to inhibit the incorporation of the sodium ion by capping off the sodium binding pocket to not allow sodium to enter from the top. W321 uses van der Walls interactions with other amino acids in the binding pocket to place it in the conformation necessary to complete this task.
==Clinical Relevance==
NTSR1 is commonly expressed in various invasive [https://en.wikipedia.org/wiki/Cancer cancer] cell lines. It is prevalent in the [https://en.wikipedia.org/wiki/Colorectal_cancer colon cancer] [https://en.wikipedia.org/wiki/Adenocarcinoma adenocarcinoma], but is not found in adult colon cell types. NTSR1 is also found in aggressive [https://en.wikipedia.org/wiki/Prostate_cancer prostate cancer] cells, but not [https://en.wikipedia.org/wiki/Epithelium epithelial] prostate cells. In prostate cancer cells, binding of the NTS results in [https://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase mitogen-activated protein kinase (PKB)], [https://en.wikipedia.org/wiki/Phosphoinositide_3-kinase phosphoinositide-3 kinase (PI-3K)], [https://en.wikipedia.org/wiki/Epidermal_growth_factor_receptor epidermal growth factor receptor (EGFR)], [https://en.wikipedia.org/wiki/Proto-oncogene_tyrosine-protein_kinase_Src SRC], and [https://en.wikipedia.org/wiki/STAT5 STAT5] phosphorylation. These all result in increased DNA sythesis, [https://en.wikipedia.org/wiki/Cell_growth cell proliferation], and survival. Inhibition of NTSR1 and its downstream signaling represents a target for radiotherapy. NTSR1 can be inhibited by agonist meclinertant which has shown evidence for the inhibition of proliferation and prosurvival of cancer cells. Treatment of radiation and meclinerant has shown to provide selective treatment of cancer cells over normal cells, indicating the need for clinical trials of this approach. <ref name="Valerie">PMID:21903767</ref> <ref name="Kisfalvi">PMID:19679549</ref>

</StructureSection>
== References ==
<references/>

Sandbox reserved 1169

2016-03-29T13:48:24Z

Andrew Koelper:

==Neurotensin Receptor (''Rattus norvegicus'')==
<StructureSection load='4GRV2.pdb' size='340' side='right' caption='Neurotensin G-Protein Coupled Receptor' scene='72/721539/Overall_structure/3'>
== Introduction ==
The neurotensin receptor (NTSR1) belongs to the superfamily of proteins known as [http://proteopedia.org/wiki/index.php/G_protein-coupled_receptor G protein-coupled receptors] (GPCRs) and responds to the 13 amino acid hormone [https://en.wikipedia.org/wiki/Neurotensin neurotensin] (NTS). There are currently around 800 G protein-coupled receptors that have been identified and are thought to be responsible for roughly 80% of [https://en.wikipedia.org/wiki/Signal_transduction signal transduction] across the cell membrane.<ref name="Millar">PMID:20019124</ref> These receptors are involved in a vast array of physiological processes within the body that range from interactions with [https://en.wikipedia.org/wiki/Dopamine dopamine] to effects on secretion of bile in the intestines.<ref name="Gui">PMID:11208724</ref> <ref name="Binder">PMID:1173461</ref> Due to the vast array of functions that these proteins serve and their high abundance within the body, these proteins have become a major site of drug targets in medicine making a deeper, more in depth understanding of these proteins very important. <ref name="Fang">PMID:23573662</ref> There are currently no NTRS1 structures of the inactive state, so there is no way to determine the [https://en.wikipedia.org/wiki/Conformational_change conformational change] of the binding pocket caused by the binding of NTS. <ref name="White">PMID:23051748</ref>
== Neurotensin ==
<scene name='72/721539/Nts8_13/1'>Neurotensin(NTS)</scene> is a 13-amino acid peptide originally isolated from [https://en.wikipedia.org/w/index.php?title=Bovinae&redirect=no bovine] [https://en.wikipedia.org/wiki/Hypothalamus hypothalamus]. It fulfills the role of both a [https://en.wikipedia.org/wiki/Neurotransmitter neurotransmitter] and a [https://en.wikipedia.org/wiki/Neuromodulation neuromodulator] in the nervous system and a [https://en.wikipedia.org/wiki/Hormone hormone] in the periphery. NTS is a neuromodulator of dopamine transmission and of anterior [https://en.wikipedia.org/wiki/Pituitary_gland pituitary] hormone secretion. It is also a [https://en.wikipedia.org/w/index.php?title=Paracrine_signalling&redirect=no paracrine] and [https://en.wikipedia.org/wiki/Endocrine_system endocrine] modulator in the periphery of the digestive tract and cardiovascular system. Finally, NTS serves as a [https://en.wikipedia.org/wiki/Growth_factor growth factor] for many normal and cancerous cell types.<ref name="Vincent">PMID:10390649</ref>

Only the C-terminal tail of NTS, amino acids 8-13, were resolved in the crystal structure.
== Structure ==
=== Overall Structure ===
[[Image:Image of structure of G protein coupled receptor.jpg |100 px|left|thumb|G protein across membrane ]]
Like other G protein-coupled receptors, the neurotensin receptor is composed of 3 distinct regions. An extracellular binding site where neurotensin binds and causes a conformational change of the protein, a region containing <scene name='72/727765/Overall_structure/1'>7 transmembrane alpha helices</scene> that transduce the signal from the extracellular side of the cell membrane to the intracellular side, and an intracellular region that, when activated by a conformational change in the protein, activates a [https://en.wikipedia.org/wiki/G_protein G protein] associated with this receptor. There are currently no crystal structures of the inactive form of the neurotensin receptor available. Without a representation of the inactive form, the conformational changes caused by agonist binding are still not completely known.
=== Neurotensin Binding Site ===
Binding of NTS to the binding site is enriched by <scene name='72/721539/Binding_pocket_surface/3'>charge complementarity</scene> between the positive NTS arginine side chains and the electronegative pocket. In addition, the C-terminus forms a <scene name='72/721539/Binding_site_charges/2'>salt bridge</scene> with R328. Only three out of eight hydrogen bonds are made between the side chains of NTS and the receptor. Most of the interactions are van der Waals interactions. The binding pocket is partially capped by a β-hairpin loop at the proximal end of the receptor protein's N-terminus.<ref name="White"/>
=== Hydrophobic Stacking ===
A major player in the transduction of the extracellular signal to the intracellular G protein is the <scene name='72/727765/Hydrogen_bonding_network/1'>hydrogen bonding network</scene> that links the bound hormone with the hydrophobic core of the neurotensin receptor. The carboxylate of L13 forms a hydrogen bond network with R327, R328, and Y324. The Y324, in turn, is brought into an orientation to make the formation of a <scene name='72/727765/Hydrophobic_stacking_4xee/1'>hydrophobic stacking</scene> network between F358, W321, A157, and F317 possible.<ref name="Krumm">PMID:23051748</ref> The conformational changes caused by this stacking allows for the signal to be moved from the extracellular binding site through the transmembrane helices of the receptor to the intracellular region activating the G protein.
== Sodium Binding Pocket ==
Conserved across all class A GPCRs, a <scene name='72/727765/Gw5_na_pocket_final/2'>sodium ion-binding pocket</scene> is seen in the middle of TM2 helix. The ion is coordinated with a highly conserved D2.50 and four other contacts with oxygen atoms. Some of these oxygen atoms are sourced from water molecules. In order for G-protein activation, a <scene name='72/721539/4xee_na_binding_pocket/1'>hydrogen bond network</scene> with T3.39, S7.46 ,N7.49 of the NPxxY motif, prevents the coordination of a Na+. <ref name="Krumm"/><ref name="Katritch">PMID:24767681</ref>
=== Allosteric Effects ===
Sodium ions are a negative allosteric inhibitor to the binding of the neurotensin agonist to the binding site on the neurotensin receptor. D113 of the highly conserved D/RY motif and N365 of the highly conserved NPxxY motif form a substantial hydrogen bonding network with T156 and S362.<ref name="Krumm"/> This hydrogen bonding network prevents the incorporation of the sodium ion by collapsing upon itself and therefor filling the sodium binding pocket. W321 also works to inhibit the incorporation of the sodium ion by capping off the sodium binding pocket to not allow sodium to enter from the top. W321 uses van der Walls interactions with other amino acids in the binding pocket to place it in the conformation necessary to complete this task.
==Clinical Relevance==
NTSR1 is commonly expressed in various invasive cancer cell lines. It is prevalent in the colon cancer adenocarcinoma, but is not found in adult colon cell types. NTSR1 is also found in aggressive prostate cancer cells, but not epithelial prostate cells. In prostate cancer cells, binding of the NTS results in mitogen-activated protein kinase (PKB), phosphoinositide-3 kinase (PI-3K), epidermal growth factor receptor (EGFR), SRC, and STAT5 phosphorylation. These all result in increased DNA sythesis, cell proliferation, and survival.

http://cancerres.aacrjournals.org/content/71/21/6817.long
http://cancerres.aacrjournals.org/content/69/16/6539.full.pdf+html

</StructureSection>
== References ==
<references/>

Sandbox reserved 1169

2016-03-29T13:46:58Z

Andrew Koelper:

==Neurotensin Receptor (''Rattus norvegicus'')==
<StructureSection load='4GRV2.pdb' size='340' side='right' caption='Neurotensin G-Protein Coupled Receptor' scene='72/721539/Overall_structure/3'>
== Introduction ==
The neurotensin receptor (NTSR1) belongs to the superfamily of proteins known as [http://proteopedia.org/wiki/index.php/G_protein-coupled_receptor G protein-coupled receptors] (GPCRs) and responds to the 13 amino acid hormone [https://en.wikipedia.org/wiki/Neurotensin neurotensin] (NTS). There are currently around 800 G protein-coupled receptors that have been identified and are thought to be responsible for roughly 80% of [https://en.wikipedia.org/wiki/Signal_transduction signal transduction] across the cell membrane.<ref name="Millar">PMID:20019124</ref> These receptors are involved in a vast array of physiological processes within the body that range from interactions with [https://en.wikipedia.org/wiki/Dopamine dopamine] to effects on secretion of bile in the intestines.<ref name="Gui">PMID:11208724</ref> <ref name="Binder">PMID:1173461</ref> Due to the vast array of functions that these proteins serve and their high abundance within the body, these proteins have become a major site of drug targets in medicine making a deeper, more in depth understanding of these proteins very important. <ref name="Fang">PMID:23573662</ref> There are currently no NTRS1 structures of the inactive state, so there is no way to determine the [https://en.wikipedia.org/wiki/Conformational_change conformational change] of the binding pocket caused by the binding of NTS. <ref name="White">PMID:23051748</ref>
== Neurotensin ==
<scene name='72/721539/Nts8_13/1'>Neurotensin(NTS)</scene> is a 13-amino acid peptide originally isolated from [https://en.wikipedia.org/w/index.php?title=Bovinae&redirect=no bovine] [https://en.wikipedia.org/wiki/Hypothalamus hypothalamus]. It fulfills the role of both a [https://en.wikipedia.org/wiki/Neurotransmitter neurotransmitter] and a [https://en.wikipedia.org/wiki/Neuromodulation neuromodulator] in the nervous system and a [https://en.wikipedia.org/wiki/Hormone hormone] in the periphery. NTS is a neuromodulator of dopamine transmission and of anterior [https://en.wikipedia.org/wiki/Pituitary_gland pituitary] hormone secretion. It is also a [https://en.wikipedia.org/w/index.php?title=Paracrine_signalling&redirect=no paracrine] and [https://en.wikipedia.org/wiki/Endocrine_system endocrine] modulator in the periphery of the digestive tract and cardiovascular system. Finally, NTS serves as a [https://en.wikipedia.org/wiki/Growth_factor growth factor] for many normal and cancerous cell types.<ref name="Vincent">PMID:10390649</ref>

Only the C-terminal tail of NTS, amino acids 8-13, were resolved in the crystal structure.
== Structure ==
=== Overall Structure ===
[[Image:Image of structure of G protein coupled receptor.jpg |100 px|left|thumb|G protein across membrane ]]
Like other G protein-coupled receptors, the neurotensin receptor is composed of 3 distinct regions. An extracellular binding site where neurotensin binds and causes a conformational change of the protein, a region containing <scene name='72/727765/Overall_structure/1'>7 transmembrane alpha helices</scene> that transduce the signal from the extracellular side of the cell membrane to the intracellular side, and an intracellular region that, when activated by a conformational change in the protein, activates a [https://en.wikipedia.org/wiki/G_protein G protein] associated with this receptor. There are currently no crystal structures of the inactive form of the neurotensin receptor available. Without a representation of the inactive form, the conformational changes caused by agonist binding are still not completely known.
=== Neurotensin Binding Site ===
Binding of NTS to the binding site is enriched by <scene name='72/721539/Binding_pocket_surface/3'>charge complementarity</scene> between the positive NTS arginine side chains and the electronegative pocket. In addition, the C-terminus forms a <scene name='72/721539/Binding_site_charges/2'>salt bridge</scene> with R328. Only three out of eight hydrogen bonds are made between the side chains of NTS and the receptor. Most of the interactions are van der Waals interactions. The binding pocket is partially capped by a β-hairpin loop at the proximal end of the receptor protein's N-terminus.<ref name="White"/>
=== Hydrophobic Stacking ===
A major player in the transduction of the extracellular signal to the intracellular G protein is the <scene name='72/727765/Hydrogen_bonding_network/1'>hydrogen bonding network</scene> that links the bound hormone with the hydrophobic core of the neurotensin receptor. The carboxylate of L13 forms a hydrogen bond network with R327, R328, and Y324. The Y324, in turn, is brought into an orientation to make the formation of a <scene name='72/727765/Hydrophobic_stacking_4xee/1'>hydrophobic stacking</scene> network between F358, W321, A157, and F317 possible.<ref name="Krumm">PMID:23051748</ref> The conformational changes caused by this stacking allows for the signal to be moved from the extracellular binding site through the transmembrane helices of the receptor to the intracellular region activating the G protein.
== Sodium Binding Pocket ==
Conserved across all class A GPCRs, a <scene name='72/727765/Gw5_na_pocket_final/2'>sodium ion-binding pocket</scene> is seen in the middle of TM2 helix. The ion is coordinated with a highly conserved D2.50 and four other contacts with oxygen atoms. Some of these oxygen atoms are sourced from water molecules. In order for G-protein activation, a <scene name='72/721539/4xee_na_binding_pocket/1'>hydrogen bond network</scene> with T3.39, S7.46 ,N7.49 of the NPxxY motif, prevents the coordination of a Na+. <ref name="Krumm"/><ref name="Katritch">PMID:24767681</ref>
=== Allosteric Effects ===
Sodium ions are a negative allosteric inhibitor to the binding of the neurotensin agonist to the binding site on the neurotensin receptor. D113 of the highly conserved D/RY motif and N365 of the highly conserved NPxxY motif form a substantial hydrogen bonding network with T156 and S362.<ref name="Krumm"/> This hydrogen bonding network prevents the incorporation of the sodium ion by collapsing upon itself and therefor filling the sodium binding pocket. W321 also works to inhibit the incorporation of the sodium ion by capping off the sodium binding pocket to not allow sodium to enter from the top. W321 uses van der Walls interactions with other amino acids in the binding pocket to place it in the conformation necessary to complete this task.
==Clinical Relevance==
NTSR1 is commonly expressed in various invasive cancer cell lines. It is prevalent in the colon cancer adenocarcinoma, but is not found in adult colon cell types. NTSR1 is also found in aggressive prostate cancer cells, but not epithelial prostate cells. In prostate cancer cells, binding of the NTS results in mitogen-activated protein kinase (PKB), phosphoinositide-3 kinase (PI-3K), epidermal growth factor receptor (EGFR), SRC, and STAT5 phosphorylation. These all result in increased DNA sythesis, cell proliferation, and survival.

http://cancerres.aacrjournals.org/content/71/21/6817.long

</StructureSection>
== References ==
<references/>

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==Neurotensin Receptor (''Rattus norvegicus'')==
<StructureSection load='4GRV2.pdb' size='340' side='right' caption='Neurotensin G-Protein Coupled Receptor' scene='72/721539/Overall_structure/3'>
== Introduction ==
The neurotensin receptor (NTSR1) belongs to the superfamily of proteins known as [http://proteopedia.org/wiki/index.php/G_protein-coupled_receptor G protein-coupled receptors] (GPCRs) and responds to the 13 amino acid hormone neurotensin (NTS). There are currently around 800 G protein-coupled receptors that have been identified and are thought to be responsible for roughly 80% of signal transduction across the cell membrane.<ref name="Millar">PMID:20019124</ref> These receptors are involved in a vast array of physiological processes within the body that range from interactions with dopamine to effects on secretion of bile in the intestines.<ref name="Gui">PMID:11208724</ref> <ref name="Binder">PMID:1173461</ref> Due to the vast array of functions that these proteins serve and their high abundance within the body, these proteins have become a major site of drug targets in medicine making a deeper, more in depth understanding of these proteins very important. <ref name="Fang">PMID:23573662</ref> There are currently no NTRS1 structures of the inactive state, so there is no way to determine the conformational changes of the binding pocket caused by the binding of NTS. <ref name="White">PMID:23051748</ref>
== Neurotensin ==
<scene name='72/721539/Nts8_13/1'>Neurotensin(NTS)</scene> is a 13-amino acid peptide originally isolated from bovine hypothalamus. It fulfills the role of both a neurotransmitter and a neuromodulator in the nervous system and a hormone in the periphery. NTS is a neuromodulator of dopamine transmission and of anterior pituitary hormone secretion. It is also a paracrine and endocrine modulator in the periphery of the digestive tract and cardiovascular system. Finally, NTS serves as a growth factor for many normal and cancerous cell types.(Neurotensin and
neurotensin receptors
Jean-Pierre Vincent, Jean Mazella and Patrick Kitabgi)

Only the C-terminal tail of NTS, amino acids 8-13, were resolved in the crystal structure.
== Structure ==
=== Overall Structure ===
[[Image:Image of structure of G protein coupled receptor.jpg |100 px|left|thumb|G protein across membrane ]]
Like other G protein-coupled receptors, the neurotensin receptor is composed of 3 distinct regions. An extracellular binding site where neurotensin binds and causes a conformational change of the protein, a region containing <scene name='72/727765/Overall_structure/1'>7 transmembrane alpha helices</scene> that transduce the signal from the extracellular side of the cell membrane to the intracellular side, and an intracellular region that, when activated by a conformational change in the protein, activates a [https://en.wikipedia.org/wiki/G_protein G protein] associated with this receptor. There are currently no crystal structures of the inactive form of the neurotensin receptor available. Without a representation of the inactive form, the conformational changes caused by agonist binding are still not completely known.
=== Neurotensin Binding Site ===
Binding of NTS to the binding site is enriched by <scene name='72/721539/Binding_pocket_surface/3'>charge complementarity</scene> between the positive NTS arginine side chains and the electronegative pocket. In addition, the C-terminus forms a <scene name='72/721539/Binding_site_charges/2'>salt bridge</scene> with R328. Only three out of eight hydrogen bonds are made between the side chains of NTS and the receptor. Most of the interactions are van der Waals interactions. The binding pocket is partially capped by a β-hairpin loop at the proximal end of the receptor protein's N-terminus. (White)
=== Hydrophobic Stacking ===
A major player in the transduction of the extracellular signal to the intracellular G protein is the <scene name='72/727765/Hydrogen_bonding_network/1'>hydrogen bonding network</scene> that links the bound hormone with the hydrophobic core of the neurotensin receptor. The carboxylate of L13 forms a hydrogen bond network with R327, R328, and Y324. The Y324, in turn, is brought into an orientation to make the formation of a <scene name='72/727765/Hydrophobic_stacking_4xee/1'>hydrophobic stacking</scene> network between F358, W321, A157, and F317 possible.<ref name="Krumm">PMID:23051748</ref> The conformational changes caused by this stacking allows for the signal to be moved from the extracellular binding site through the transmembrane helices of the receptor to the intracellular region activating the G protein.
== Sodium Binding Pocket ==
Conserved across all class A GPCRs, a <scene name='72/727765/Gw5_na_pocket_final/2'>sodium ion-binding pocket</scene> is seen in the middle of TM2 helix. The ion is coordinated with a highly conserved D2.50 and four other contacts with oxygen atoms. Some of these oxygen atoms are sourced from water molecules. In order for G-protein activation, a <scene name='72/721539/4xee_na_binding_pocket/1'>hydrogen bond network</scene> with T3.39, S7.46 ,N7.49 of the NPxxY motif, prevents the coordination of a Na+. (Krumm)(Allosteric sodium in class A GPCR signaling Vsevolod Katritch, Gustavo Fenalti, Enrique E. Abola, Bryan L. Roth, Vadim Cherezov, and Raymond C. Stevens)
=== Allosteric Effects ===
Sodium ions are a negative allosteric inhibitor to the binding of the neurotensin agonist to the binding site on the neurotensin receptor. D113 of the highly conserved D/RY motif and N365 of the highly conserved NPxxY motif form a substantial hydrogen bonding network with T156 and S362. This hydrogen bonding network prevents the incorporation of the sodium ion by collapsing upon itself and therefor filling the sodium binding pocket. W321 also works to inhibit the incorporation of the sodium ion by capping off the sodium binding pocket to not allow sodium to enter from the top. W321 uses van der Walls interactions with other amino acids in the binding pocket to place it in the conformation necessary to complete this task.

</StructureSection>
== References ==
<references/>

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==Neurotensin Receptor (''Rattus norvegicus'')==
<StructureSection load='4GRV2.pdb' size='340' side='right' caption='Neurotensin G-Protein Coupled Receptor' scene='72/721539/Overall_structure/3'>
== Introduction ==
The neurotensin receptor (NTSR1) belongs to the superfamily of proteins known as [http://proteopedia.org/wiki/index.php/G_protein-coupled_receptor G protein-coupled receptors] (GPCRs) and responds to the 13 amino acid hormone neurotensin (NT). There are currently around 800 G protein-coupled receptors that have been identified and are thought to be responsible for roughly 80% of signal transduction across the cell membrane.<ref name="Millar">PMID:20019124</ref> These receptors are involved in a vast array of physiological processes within the body that range from interactions with dopamine to effects on secretion of bile in the intestines.<ref name="Gui">PMID:11208724</ref> <ref name="Binder">PMID:1173461</ref> Due to the vast array of functions that these proteins serve and their high abundance within the body, these proteins have become a major site of drug targets in medicine making a deeper, more in depth understanding of these proteins very important. <ref name="Fang">PMID:23573662</ref> There are currently no NTRS1 structures of the inactive state, so there is no way to determine the conformational changes of the binding pocket caused by the binding of NT. <ref name="White">PMID:23051748</ref>
== Neurotensin ==
<scene name='72/721539/Nts8_13/1'>Neurotensin(NTS)</scene> is a 13-amino acid peptide originally isolated from bovine hypothalamus. It fulfills the role of both a neurotransmitter and a neuromodulator in the nervous system and a hormone in the periphery. NTS is a neuromodulator of dopamine transmission and of anterior pituitary hormone secretion. It is also a paracrine and endocrine modulator in the periphery of the digestive tract and cardiovascular system. Finally, NTS serves as a growth factor for many normal and cancerous cell types.(Neurotensin and
neurotensin receptors
Jean-Pierre Vincent, Jean Mazella and Patrick Kitabgi)

Only the C-terminal tail of NTS, amino acids 8-13, were resolved in the crystal structure.
== Structure ==
=== Overall Structure ===
[[Image:Image of structure of G protein coupled receptor.jpg |100 px|left|thumb|G protein across membrane ]]
Like other G protein-coupled receptors, the neurotensin receptor is composed of 3 distinct regions. An extracellular binding site where neurotensin binds and causes a conformational change of the protein, a region containing <scene name='72/727765/Overall_structure/1'>7 transmembrane alpha helices</scene> that transduce the signal from the extracellular side of the cell membrane to the intracellular side, and an intracellular region that, when activated by a conformational change in the protein, activates a [https://en.wikipedia.org/wiki/G_protein G protein] associated with this receptor. There are currently no crystal structures of the inactive form of the neurotensin receptor available. Without a representation of the inactive form, the conformational changes caused by agonist binding are still not completely known.
=== Neurotensin Binding Site ===
Binding of NTS to the binding site is enriched by <scene name='72/721539/Binding_pocket_surface/3'>charge complementarity</scene> between the positive NTS arginine side chains and the electronegative pocket. In addition, the C-terminus forms a <scene name='72/721539/Binding_site_charges/2'>salt bridge</scene> with R328. Only three out of eight hydrogen bonds are made between the side chains of NTS and the receptor. Most of the interactions are van der Waals interactions. The binding pocket is partially capped by a β-hairpin loop at the proximal end of the receptor protein's N-terminus. (White)
=== Hydrophobic Stacking ===
A major player in the transduction of the extracellular signal to the intracellular G protein is the <scene name='72/727765/Hydrogen_bonding_network/1'>hydrogen bonding network</scene> that links the bound hormone with the hydrophobic core of the neurotensin receptor. The carboxylate of L13 forms a hydrogen bond network with R327, R328, and Y324. The Y324, in turn, is brought into an orientation to make the formation of a <scene name='72/727765/Hydrophobic_stacking_4xee/1'>hydrophobic stacking</scene> network between F358, W321, A157, and F317 possible.<ref name="Krumm">PMID:23051748</ref> The conformational changes caused by this stacking allows for the signal to be moved from the extracellular binding site through the transmembrane helices of the receptor to the intracellular region activating the G protein.
== Sodium Binding Pocket ==
Conserved across all class A GPCRs, a <scene name='72/727765/Gw5_na_pocket_final/2'>sodium ion-binding pocket</scene> is seen in the middle of TM2 helix. The ion is coordinated with a highly conserved D2.50 and four other contacts with oxygen atoms. Some of these oxygen atoms are sourced from water molecules. In order for G-protein activation, a <scene name='72/721539/4xee_na_binding_pocket/1'>hydrogen bond network</scene> with T3.39, S7.46 ,N7.49 of the NPxxY motif, prevents the coordination of a Na+. (Krumm)(Allosteric sodium in class A GPCR signaling Vsevolod Katritch, Gustavo Fenalti, Enrique E. Abola, Bryan L. Roth, Vadim Cherezov, and Raymond C. Stevens)
=== Allosteric Effects ===
Sodium ions are a negative allosteric inhibitor to the binding of the neurotensin agonist to the binding site on the neurotensin receptor. D113 of the highly conserved D/RY motif and N365 of the highly conserved NPxxY motif form a substantial hydrogen bonding network with T156 and S362. This hydrogen bonding network prevents the incorporation of the sodium ion by collapsing upon itself and therefor filling the sodium binding pocket. W321 also works to inhibit the incorporation of the sodium ion by capping off the sodium binding pocket to not allow sodium to enter from the top. W321 uses van der Walls interactions with other amino acids in the binding pocket to place it in the conformation necessary to complete this task.

</StructureSection>
== References ==
<references/>

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{{Sandbox_Reserved_CH462_Central_Metabolism}}
==Structure==
<StructureSection load='4GRV2.pdb' size='340' side='right' caption='Neurotensin G-Protein Coupled Receptor' scene='72/721539/Overall_structure/3'>
This is a default text for your page ''''''. Click above on '''edit this page''' to modify. Be careful with the < and > signs.
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.

== Neurotensin==
<scene name='72/721539/Nts8_13/1'>Neurotensin(NTS)</scene> is a 13-amino acid peptide originally isolated from bovine hypothalamus. It fulfills the role of both a neurotransmitter and a neuromodulator in the nervous system and a hormone in the periphery. NTS is a neuromodulator of dopamine transmission and of anterior pituitary hormone secretion. It is also a paracrine and endocrine modulator in the periphery of the digestive tract and cardiovascular system. Finally, NTS serves as a growth factor for many normal and cancerous cell types.(Vincent)

Only the C-terminal tail of NTS, amino acids 8-13, were resolved in the crystal structure.

== Binding Site ==
Binding of NTS to the binding site is enriched by <scene name='72/721539/Binding_pocket_surface/3'>charge complementarity</scene> between the positive NTS arginine side chains and the electronegative pocket. In addition, the C-terminus forms a <scene name='72/721539/Binding_site_charges/2'>salt bridge</scene> with R328. Only three out of eight hydrogen bonds are made between the side chains of NTS and the receptor. Most of the interactions are van der Waals interactions. The binding pocket is partially capped by a hairpin loop at the proximal end of the receptor protein's N-terminus. (White)

== Na+ Binding Site ==
Conserved across all class A GPCRs, a sodium ion-binding pocket is seen in the middle of TM2 helix. The ion is coordinated with a highly conserved D2.50 and four other contacts with oxygen atoms. Some of these oxygen atoms are sourced from water molecules. In order for G-protein activation, a hydrogen bond network with T3.39, S7.46 ,N7.49 of the NPxxY motif, prevents the coordination of a Na+.

== Function ==

<scene name='72/721539/4xee_na_binding_pocket/1'>4xee Sodium Binding Pocket</scene>
== Disease ==

== Relevance ==

== Structural highlights ==

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.

</StructureSection>
== References ==
<references/>

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{{Sandbox_Reserved_CH462_Central_Metabolism}}
==Structure==
<StructureSection load='4GRV2.pdb' size='340' side='right' caption='Neurotensin G-Protein Coupled Receptor' scene='72/721539/Overall_structure/3'>
This is a default text for your page ''''''. Click above on '''edit this page''' to modify. Be careful with the < and > signs.
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.

== Neurotensin==
<scene name='72/721539/Nts8_13/1'>Neurotensin(NTS)</scene> is a 13-amino acid peptide originally isolated from bovine hypothalamus. It fulfills the role of both a neurotransmitter and a neuromodulator in the nervous system and a hormone in the periphery. NTS is a neuromodulator of dopamine transmission and of anterior pituitary hormone secretion. It is also a paracrine and endocrine modulator in the periphery of the digestive tract and cardiovascular system. Finally, NTS serves as a growth factor for many normal and cancerous cell types.(Vincent)

Only the C-terminal tail of NTS, amino acids 8-13, were resolved in the crystal structure.

== Binding Site ==
Binding of NTS to the binding site is enriched by <scene name='72/721539/Binding_pocket_surface/2'>charge complementarity</scene> between the positive NTS arginine side chains and the electronegative pocket. In addition, the C-terminus forms a <scene name='72/721539/Binding_site_charges/2'>salt bridge</scene> with R328. Only three out of eight hydrogen bonds are made between the side chains of NTS and the receptor. Most of the interactions are van der Waals interactions. The binding pocket is partially capped by a hairpin loop at the proximal end of the receptor protein's N-terminus. (White)

== Na+ Binding Site ==
Conserved across all class A GPCRs, a sodium ion-binding pocket is seen in the middle of TM2 helix. The ion is coordinated with a highly conserved D2.50 and four other contacts with oxygen atoms. Some of these oxygen atoms are sourced from water molecules. In order for G-protein activation, a hydrogen bond network with T3.39, S7.46 ,N7.49 of the NPxxY motif, prevents the coordination of a Na+.

== Function ==

<scene name='72/721539/4xee_na_binding_pocket/1'>4xee Sodium Binding Pocket</scene>
== Disease ==

== Relevance ==

== Structural highlights ==

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.

</StructureSection>
== References ==
<references/>

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{{Sandbox_Reserved_CH462_Central_Metabolism}}
==Structure==
<StructureSection load='4GRV2.pdb' size='340' side='right' caption='Neurotensin G-Protein Coupled Receptor' scene='72/721539/Overall_structure/3'>
This is a default text for your page ''''''. Click above on '''edit this page''' to modify. Be careful with the < and > signs.
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.

== Neurotensin==
<scene name='72/721539/Nts8_13/1'>Neurotensin(NTS)</scene> is a 13-amino acid peptide originally isolated from bovine hypothalamus. It fulfills the role of both a neurotransmitter and a neuromodulator in the nervous system and a hormone in the periphery. NTS is a neuromodulator of dopamine transmission and of anterior pituitary hormone secretion. It is also a paracrine and endocrine modulator in the periphery of the digestive tract and cardiovascular system. Finally, NTS serves as a growth factor for many normal and cancerous cell types.(Vincent)

Only the C-terminal tail of NTS, amino acids 8-13, were resolved in the crystal structure.

== Binding Site ==
Binding of NTS to the binding site is enriched by <scene name='72/721539/Binding_pocket_surface/2'>charge complementarity</scene> between the positive NTS arginine side chains and the electronegative pocket. In addition, the C-terminus forms a <scene name='72/721539/Binding_site_charges/2'>salt bridge</scene> with R328. Only three out of eight hydrogen bonds are made between the side chains of NTS and the receptor. Most of the interactions are van der Waals interactions. The binding pocket is partially capped by a hairpin loop at the proximal end of the receptor protein's N-terminus. (White)

== Na+<\sup> Binding Site ==
Conserved across all class A GPCRs, a sodium ion-binding pocket is seen in the middle of TM2 helix. The ion is coordinated with a highly conserved D2.50<\sup> and four other contacts with oxygen atoms. Some of these oxygen atoms are sourced from water molecules. In order for G-protein activation, a hydrogen bond network with T3.39<\sup>, S7.46<\sup> ,N7.49<\sup> of the NPxxY motif, prevents the coordination of a Na+<\sup>.

== Function ==

<scene name='72/721539/4xee_na_binding_pocket/1'>4xee Sodium Binding Pocket</scene>
== Disease ==

== Relevance ==

== Structural highlights ==

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.

</StructureSection>
== References ==
<references/>

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{{Sandbox_Reserved_CH462_Central_Metabolism}}
==Structure==
<StructureSection load='4GRV2.pdb' size='340' side='right' caption='Neurotensin G-Protein Coupled Receptor' scene='72/721539/Overall_structure/3'>
This is a default text for your page ''''''. Click above on '''edit this page''' to modify. Be careful with the < and > signs.
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.

== Neurotensin==
<scene name='72/721539/Nts8_13/1'>Neurotensin(NTS)</scene> is a 13-amino acid peptide originally isolated from bovine hypothalamus. It fulfills the role of both a neurotransmitter and a neuromodulator in the nervous system and a hormone in the periphery. NTS is a neuromodulator of dopamine transmission and of anterior pituitary hormone secretion. It is also a paracrine and endocrine modulator in the periphery of the digestive tract and cardiovascular system. Finally, NTS serves as a growth factor for many normal and cancerous cell types.(Vincent)

Only the C-terminal tail of NTS, amino acids 8-13, were resolved in the crystal structure.

== Binding Site ==
Binding of NTS to the binding site is enriched by <scene name='72/721539/Binding_pocket_surface/2'>charge complementarity</scene> between the positive NTS arginine side chains and the electronegative pocket. In addition, the C-terminus forms a <scene name='72/721539/Binding_site_charges/2'>salt bridge</scene> with R328. Only three out of eight hydrogen bonds are made between the side chains of NTS and the receptor. Most of the interactions are van der Waals interactions. The binding pocket is partially capped by a hairpin loop at the proximal end of the receptor protein's N-terminus. (White)

== Function ==

<scene name='72/721539/4xee_na_binding_pocket/1'>4xee Sodium Binding Pocket</scene>
== Disease ==

== Relevance ==

== Structural highlights ==

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.

</StructureSection>
== References ==
<references/>

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{{Sandbox_Reserved_CH462_Central_Metabolism}}
==Structure==
<StructureSection load='4GRV2.pdb' size='340' side='right' caption='Neurotensin G-Protein Coupled Receptor' scene='72/721539/Overall_structure/3'>
This is a default text for your page ''''''. Click above on '''edit this page''' to modify. Be careful with the < and > signs.
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.

== Neurotensin==
<scene name='72/721539/Nts8_13/1'>Neurotensin(NTS)</scene> is a 13-amino acid peptide originally isolated from bovine hypothalamus. It fulfills the role of both a neurotransmitter and a neuromodulator in the nervous system and a hormone in the periphery. NTS is a neuromodulator of dopamine transmission and of anterior pituitary hormone secretion. It is also a paracrine and endocrine modulator in the periphery of the digestive tract and cardiovascular system. Finally, NTS serves as a growth factor for many normal and cancerous cell types.(Vincent)

Only the C-terminal tail of NTS, amino acids 8-13, were resolved in the crystal structure.

== Binding Site ==
Binding of NTS to the binding site is enriched by <scene name='72/721539/Binding_pocket_surface/2'>charge complementarity</scene> between the positive NTS arginine side chains and the electronegative pocket. In addition, the C-terminus forms a <scene name='72/721539/Binding_site_charges/2'>salt bridge</scene> with R327.
== Function ==

<scene name='72/721539/4xee_na_binding_pocket/1'>4xee Sodium Binding Pocket</scene>
== Disease ==

== Relevance ==

== Structural highlights ==

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.

</StructureSection>
== References ==
<references/>

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