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-Structure paper
タイトル | Structural insights into ligand recognition and activation of the melanocortin-4 receptor. |
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ジャーナル・号・ページ | Cell Res, Vol. 31, Issue 11, Page 1163-1175, Year 2021 |
掲載日 | 2021年8月25日 |
![]() | Huibing Zhang / Li-Nan Chen / Dehua Yang / Chunyou Mao / Qingya Shen / Wenbo Feng / Dan-Dan Shen / Antao Dai / Shanshan Xie / Yan Zhou / Jiao Qin / Jin-Peng Sun / Daniel H Scharf / Tingjun Hou / Tianhua Zhou / Ming-Wei Wang / Yan Zhang / ![]() ![]() |
PubMed 要旨 | 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 ...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 protein stimulated by the endogenous peptide ligand α-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. |
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手法 | EM (単粒子) |
解像度 | 3.0 - 3.1 Å |
構造データ | EMDB-31456, PDB-7f53: EMDB-31457, PDB-7f54: EMDB-31458, PDB-7f55: EMDB-31461, PDB-7f58: |
化合物 | ![]() ChemComp-CA: ![]() ChemComp-HOH: ![]() ChemComp-1I8: |
由来 |
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![]() | MEMBRANE PROTEIN / single particle / Class A G-protein-coupled receptors |