7f55: Difference between revisions
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==Cryo-EM structure of bremelanotide-MC4R-Gs_Nb35 complex== | |||
<StructureSection load='7f55' size='340' side='right'caption='[[7f55]], [[Resolution|resolution]] 3.10Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[7f55]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7F55 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7F55 FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.1Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=DPN:D-PHENYLALANINE'>DPN</scene>, <scene name='pdbligand=NLE:NORLEUCINE'>NLE</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7f55 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7f55 OCA], [https://pdbe.org/7f55 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7f55 RCSB], [https://www.ebi.ac.uk/pdbsum/7f55 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7f55 ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Melanocortin-4 receptor (MC4R) plays a central role in the regulation of energy homeostasis. Its high sequence similarity to other MC receptor family members, low agonist selectivity and the lack of structural information concerning MC4R-specific activation have hampered the development of MC4R-seletive therapeutics to treat obesity. Here, we report four high-resolution structures of full-length MC4R in complex with the heterotrimeric G(s) protein stimulated by the endogenous peptide ligand alpha-MSH, FDA-approved drugs afamelanotide (Scenesse) and bremelanotide (Vyleesi), and a selective small-molecule ligand THIQ, respectively. Together with pharmacological studies, our results reveal the conserved binding mode of peptidic agonists, the distinctive molecular details of small-molecule agonist recognition underlying receptor subtype selectivity, and a distinct activation mechanism for MC4R, thereby offering new insights into G protein coupling. Our work may facilitate the discovery of selective therapeutic agents targeting MC4R. | |||
Structural insights into ligand recognition and activation of the melanocortin-4 receptor.,Zhang H, Chen LN, Yang D, Mao C, Shen Q, Feng W, Shen DD, Dai A, Xie S, Zhou Y, Qin J, Sun JP, Scharf DH, Hou T, Zhou T, Wang MW, Zhang Y Cell Res. 2021 Nov;31(11):1163-1175. doi: 10.1038/s41422-021-00552-3. Epub 2021 , Aug 25. PMID:34433901<ref>PMID:34433901</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 7f55" style="background-color:#fffaf0;"></div> | ||
[[Category: | |||
[[Category: | ==See Also== | ||
[[Category: | *[[Alice Clark/BRCT|Alice Clark/BRCT]] | ||
[[Category: | *[[Transducin 3D structures|Transducin 3D structures]] | ||
[[Category: | == References == | ||
[[Category: | <references/> | ||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Synthetic construct]] | |||
[[Category: Chen L]] | |||
[[Category: Mao C]] | |||
[[Category: Qin J]] | |||
[[Category: Shen D]] | |||
[[Category: Shen Q]] | |||
[[Category: Yang D]] | |||
[[Category: Zhang H]] | |||
Latest revision as of 11:43, 17 October 2024
Cryo-EM structure of bremelanotide-MC4R-Gs_Nb35 complexCryo-EM structure of bremelanotide-MC4R-Gs_Nb35 complex
Structural highlights
Publication Abstract from PubMedMelanocortin-4 receptor (MC4R) plays a central role in the regulation of energy homeostasis. Its high sequence similarity to other MC receptor family members, low agonist selectivity and the lack of structural information concerning MC4R-specific activation have hampered the development of MC4R-seletive therapeutics to treat obesity. Here, we report four high-resolution structures of full-length MC4R in complex with the heterotrimeric G(s) protein stimulated by the endogenous peptide ligand alpha-MSH, FDA-approved drugs afamelanotide (Scenesse) and bremelanotide (Vyleesi), and a selective small-molecule ligand THIQ, respectively. Together with pharmacological studies, our results reveal the conserved binding mode of peptidic agonists, the distinctive molecular details of small-molecule agonist recognition underlying receptor subtype selectivity, and a distinct activation mechanism for MC4R, thereby offering new insights into G protein coupling. Our work may facilitate the discovery of selective therapeutic agents targeting MC4R. Structural insights into ligand recognition and activation of the melanocortin-4 receptor.,Zhang H, Chen LN, Yang D, Mao C, Shen Q, Feng W, Shen DD, Dai A, Xie S, Zhou Y, Qin J, Sun JP, Scharf DH, Hou T, Zhou T, Wang MW, Zhang Y Cell Res. 2021 Nov;31(11):1163-1175. doi: 10.1038/s41422-021-00552-3. Epub 2021 , Aug 25. PMID:34433901[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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