Sandbox reserved 1169: Difference between revisions
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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<sup>+</sup> within this site disrupts the coordination of the hydrogen bonds and places the receptor in its inactive form. <ref name="Katritch">PMID:24767681</ref> | 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<sup>+</sup> 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 === | === 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 activate the G-protein that is associated with | 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== | ==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> | 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> | ||
