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Structural mechanism of calcium-mediated hormone recognition and G beta interaction by the human melanocortin-1 receptor

文献类型：期刊论文

作者Ma, Shanshan1,2; Chen, Yan1,3,4; Dai, Antao; Yin, Wanchao1; Guo, Jia1,2; Yang, Dehua1,2,5; Zhou, Fulai1; Jiang, Yi1,2; Wang, Ming-Wei1,2,3,4,5,6; Xu, H. Eric1,2
刊名CELL RESEARCH
出版日期2021-08-27
页码11
ISSN号1001-0602
DOI10.1038/s41422-021-00557-y
通讯作者Wang, Ming-Wei(mwwang@simm.ac.cn) ; Xu, H. Eric(eric.xu@simm.ac.cn)
英文摘要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 hormone alpha-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 G beta subunit 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.
WOS关键词CRYO-EM STRUCTURE ; CONSTITUTIVE ACTIVITY ; LIGAND RECOGNITION ; ALPHA-MELANOTROPIN ; GLP-1 RECEPTOR ; MELANOMA-CELLS ; ACTIVATION ; POMC ; DETERMINANTS ; SELECTIVITY
资助项目Ministry of Science and Technology of China[2018YFA0507002] ; Ministry of Science and Technology of China[2018YFA0507000] ; National Natural Science Foundation of China[31770796] ; National Natural Science Foundation of China[81872915] ; National Natural Science Foundation of China[82073904] ; National Natural Science Foundation of China[81773792] ; National Natural Science Foundation of China[81973373] ; National Science and Technology Major Project of China - Key New Drug Creation and Manufacturing Program[2018ZX09711002-002-002] ; National Science and Technology Major Project of China - Key New Drug Creation and Manufacturing Program[2018ZX09735-001] ; National Science and Technology Major Project of China - Key New Drug Creation and Manufacturing Program[2018ZX09711002-002-005] ; Shanghai Municipal Science and Technology Commission Major Project[2019SHZDZX02] ; CAS Strategic Priority Research Program[XDB37030103] ; Novo Nordisk-CAS Research Fund[NNCAS-2017-1-CC]
WOS研究方向Cell Biology
语种英语
出版者SPRINGERNATURE
WOS记录号WOS:000690370400001
源URL[http://119.78.100.183/handle/2S10ELR8/297679]  
专题中国科学院上海药物研究所
通讯作者Wang, Ming-Wei; Xu, H. Eric
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai, Peoples R China
2.Univ Chinese Acad Sci, Beijing, Peoples R China
3.Fudan Univ, Sch Pharm, Shanghai, Peoples R China
4.Fudan Univ, Sch Basic Med Sci, Dept Pharmacol, Shanghai, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, Shanghai, Peoples R China
6.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China
推荐引用方式
GB/T 7714		 Ma, Shanshan,Chen, Yan,Dai, Antao,et al. Structural mechanism of calcium-mediated hormone recognition and G beta interaction by the human melanocortin-1 receptor[J]. CELL RESEARCH,2021:11.
APA Ma, Shanshan.,Chen, Yan.,Dai, Antao.,Yin, Wanchao.,Guo, Jia.,...&Xu, H. Eric.(2021).Structural mechanism of calcium-mediated hormone recognition and G beta interaction by the human melanocortin-1 receptor.CELL RESEARCH,11.
MLA Ma, Shanshan,et al."Structural mechanism of calcium-mediated hormone recognition and G beta interaction by the human melanocortin-1 receptor".CELL RESEARCH (2021):11.

入库方式： OAI收割

来源：上海药物研究所

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