Structural mechanism of calcium-mediated hormone recognition and Gβinteraction by the human melanocortin-1 receptor  

作　　者：Shanshan Ma Yan Chen Antao Dai Wanchao Yin Jia Guo Dehua Yang Fulai Zhou Yi Jiang Ming-Wei Wang H.Eric Xu 

机构地区：[1]The CAS Key Laboratory of Receptor Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai,China [2]University of Chinese Academy of Sciences,Beijing,China [3]School of Pharmacy,Fudan University,Shanghai,China [4]Department of Pharmacology,School of Basic Medical Sciences,Fudan University,Shanghai,China [5]The National Center for Drug Screening,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai,China [6]School of Life Science and Technology,ShanghaiTech University,Shanghai,China

出　　处：《Cell Research》2021年第10期1061-1071,共11页细胞研究（英文版）

基　　金：The cryo-EM data were collected at the Cryo-Electron Microscopy Research Center,Shanghai Institute of Materia Medica,Chinese Academy of Sciences.We thank the staff of the National Center for Protein Science(Shanghai)Electron Microscopy facility for instrument support.This work was partially supported by the Ministry of Science and Technology of China(2018YFA0507002 to H.E.X.and 2018YFA0507000 to M.-W.W.);the National Natural Science Foundation of China(31770796 to Y.J.,81872915 and 82073904 to M.-W.W.,81773792 and 81973373 to D.Y.);National Science and Technology Major Project of China-Key New Drug Creation and Manufacturing Program(2018ZX09711002-002-002 to Y.J.,2018ZX09735-001 to M.-W.W.,and 2018ZX09711002-002-005 to D.Y.);the Shanghai Municipal Science and Technology Commission Major Project(2019SHZDZX02 to H.E.X.);the CAS Strategic Priority Research Program(XDB37030103 to H.E.X.);Novo Nordisk-CAS Research Fund(NNCAS-2017-1-CC to D.Y.).

摘　　要：Melanocortins are peptide hormones critical for the regulation of stress response,energy homeostasis,inflammation,and skin pigmentation.Their functions are mediated by five G protein-coupled receptors(MC1R–MC5R),predominately through the stimulatory G protein(Gs).MC1R,the founding member of melanocortin receptors,is mainly expressed in melanocytes and is involved in melanogenesis.Dysfunction of MC1R is associated with the development of melanoma and skin cancer.Here we present three cryo-electron microscopy structures of the MC1R–Gs complexes bound to endogenous hormoneα-MSH,a marketed drug afamelanotide,and a synthetic agonist SHU9119.These structures reveal the orthosteric binding pocket for the conserved HFRW motif among melanocortins and the crucial role of calcium ion in ligand binding.They also demonstrate the basis of differential activities among different ligands.In addition,unexpected interactions between MC1R and the Gβsubunit were discovered from these structures.Together,our results elucidate a conserved mechanism of calcium-mediated ligand recognition,a specific mode of G protein coupling,and a universal activation pathway of melanocortin receptors.

关 键 词：MECHANISM TOGETHER FOUNDING 

分 类 号：R739.5[医药卫生—肿瘤]