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Volume 31, No 10, Oct 2021

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 31 Issue 10, October 2021: 1061-1071

ORIGINAL ARTICLES

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

Shanshan Ma1,2,† , Yan Chen1,3,4,† , Antao Dai5 , Wanchao Yin1 , Jia Guo1,2 , Dehua Yang1,2,5 , Fulai Zhou1 , Yi Jiang1,2 , Ming-Wei Wang1,2,3,4,5,6,* , H. Eric Xu1,2,6,*

1The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
2University of Chinese Academy of Sciences, Beijing, China
3School of Pharmacy, Fudan University, Shanghai, China
4Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, China
5The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
6School of Life Science and Technology, ShanghaiTech University, Shanghai, China
†These authors contributed equally: Shanshan Ma, Yan Chen
Correspondence: Ming-Wei Wang(mwwang@simm.ac.cn)H. Eric Xu(eric.xu@simm.ac.cn)

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 α-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 Gβ 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.


https://doi.org/10.1038/s41422-021-00557-y

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