7F55

Cryo-EM structure of bremelanotide-MC4R-Gs_Nb35 complex

Summary for 7F55

• Entry DOI: 10.2210/pdb7f55/pdb
• EMDB information: 31456 31457 31458 31461
• Descriptor: Isoform Gnas-2 of Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (8 entities in total)
• Functional Keywords: single particle, membrane protein, class a g-protein-coupled receptors
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 6
• Total formula weight: 164683.48

Authors

Zhang, H.,Chen, L.,Mao, C.,Shen, Q.,Yang, D.,Shen, D.,Qin, J. (deposition date: 2021-06-21, release date: 2021-11-03, Last modification date: 2024-10-16)

Primary citation

Zhang, H.,Chen, L.N.,Yang, D.,Mao, C.,Shen, Q.,Feng, W.,Shen, D.D.,Dai, A.,Xie, S.,Zhou, Y.,Qin, J.,Sun, J.P.,Scharf, D.H.,Hou, T.,Zhou, T.,Wang, M.W.,Zhang, Y.
Structural insights into ligand recognition and activation of the melanocortin-4 receptor.
Cell Res., 31:1163-1175, 2021

PubMed Abstract: 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.

PubMed: 34433901
DOI: 10.1038/s41422-021-00552-3

Experimental method

ELECTRON MICROSCOPY (3.1 Å)