Sandbox reserved 1169: Difference between revisions
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== Structure == | == Structure == | ||
=== Overall 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. | [[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 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. | 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 === | === Neurotensin Binding Site === | ||
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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 this receptor. | 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 this receptor. | ||
==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 ]]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> | ||
