Structural insights into ligand recognition and activation of the melanocortin-4 receptor  

作　　者：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 

机构地区：[1]Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital,Zhejiang University School of Medicine,Hangzhou,Zhejiang,China [2]Liangzhu Laboratory,Zhejiang University Medical Center,Hangzhou,Zhejiang,China [3]MOE Frontier Science Center for Brain Research and Brain-Machine Integration,Zhejiang University School of Medicine,Hangzhou,Zhejiang,China [4]Key Laboratory of Immunity and Inflammatory Diseases of Zhejiang Province,Hangzhou,Zhejiang,China [5]The CAS Key Laboratory of Receptor Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai,China [6]The National Center for Drug Screening,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai,China [7]University of Chinese Academy of Sciences,Beijing,China [8]School of Pharmacy,Fudan University,Shanghai,China [9]Department of Cell Biology and Cancer Institute of the Second Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou,China [10]Institute of Gastroenterology,Zhejiang University,Hangzhou,China [11]Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases,Hangzhou,Zhejiang,China [12]Department of Molecular Genetics,University of Toronto,Toronto,Ontario,Canada [13]Department of Physiology and Pathophysiology,School of Basic Medical Sciences,Peking University [14]Key Laboratory of Molecular Cardiovascular Science,Ministry of Education,Beijing,China [15]Key Laboratory Experimental Teratology of the Ministry of Education,Department of Biochemistry and Molecular Biology,School of Basic Medical Sciences,Cheeloo College of Medicine,Shandong University,Jinan,Shandong,China [16]Department of Microbiology and The Children's Hospital,Zhejiang University School of Medicine,Hangzhou,Zhejiang,China [17]Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University,College of Pharmaceutical Sciences,Zhejiang University,Hangzhou,Zhejiang,China [18]School of Life Science and Technology,ShanghaiTech University,Shanghai,China [19]Department of Pharmacol

出　　处：《Cell Research》2021年第11期1163-1175,共13页细胞研究（英文版）

基　　金：This work was partially supported by grants from the National Natural Science Foundation of China(81922071 to Y.Zhang,81872915/82073904 to M.-W.W.and 81773792/81973373 to D.Y.);the National Key Basic Research Program of China(2019YFA0508800 to Y.Zhang,2018YFA0507000 to M.-W.W.and 2018ZX09711002-002-005 to D.Y.);Zhejiang Province Science Fund for Distinguished Young Scholars(LR19H310001 to Y.Zhang);Key R&D Projects of Zhejiang Province(2021C03039 to Y.Zhang);National Science&Technology Major Project of China-Key New Drug Creation and Manufacturing Program(2018ZX09735-001 to M.-W.W.and 2018ZX09711002-002-005 to D.Y.);Novo Nordisk-CAS Research Fund(NNCAS-2017-1-CC to D.Y.).

摘　　要：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 Gs protein stimulated by the endogenous peptide ligand a-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.

关 键 词：MC4R ACTIVATION thereby 

分 类 号：Q2[生物学—细胞生物学]