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Structure paper

TitleStructural insights into ligand recognition and activation of the melanocortin-4 receptor.
Journal, issue, pagesCell Res, Vol. 31, Issue 11, Page 1163-1175, Year 2021
Publish dateAug 25, 2021
AuthorsHuibing 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 AbstractMelanocortin-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.
External linksCell Res / PubMed:34433901 / PubMed Central
MethodsEM (single particle)
Resolution3.0 - 3.1 Å
Structure data

31456

7f53

EMDB-31456, PDB-7f53:
Cryo-EM structure of a-MSH-MC4R-Gs_Nb35 complex
Method: EM (single particle) / Resolution: 3.0 Å

31457

7f54

EMDB-31457, PDB-7f54:
Cryo-EM structure of afamelanotide-MC4R-Gs_Nb35 complex
Method: EM (single particle) / Resolution: 3.0 Å

31458

7f55

EMDB-31458, PDB-7f55:
Cryo-EM structure of bremelanotide-MC4R-Gs_Nb35 complex
Method: EM (single particle) / Resolution: 3.1 Å

31461

7f58

EMDB-31461, PDB-7f58:
Cryo-EM structure of THIQ-MC4R-Gs_Nb35 complex
Method: EM (single particle) / Resolution: 3.1 Å

Chemicals

ChemComp-CA:
Unknown entry

ChemComp-HOH:
WATER

ChemComp-1I8:
(3R)-N-[(2R)-3-(4-chlorophenyl)-1-[4-cyclohexyl-4-(1,2,4-triazol-1-ylmethyl)piperidin-1-yl]-1-oxidanylidene-propan-2-yl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide / agonist*YM

Source
  • homo sapiens (human)
  • synthetic construct (others)
KeywordsMEMBRANE PROTEIN / single particle / Class A G-protein-coupled receptors

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