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

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

Posted 21 Jun 2021
bioRxiv DOI: 10.1101/2021.06.20.449193

Melanocortins are peptide hormones critical for stress response, energy homeostasis, inflammation, and skin pigmentation. Their functions are mediated by five G protein-coupled receptors (MC1R to 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 -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 provide a conserved mechanism of calcium-mediated ligand recognition, specific mode of G protein coupling, and a universal activation pathway of melanocortin receptors.

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