ジャーナル: Cell Res / 年: 2021 タイトル: Structural mechanism of calcium-mediated hormone recognition and Gβ interaction by the human melanocortin-1 receptor. 著者: Shanshan Ma / Yan Chen / Antao Dai / Wanchao Yin / Jia Guo / Dehua Yang / Fulai Zhou / Yi Jiang / Ming-Wei Wang / H Eric Xu / 要旨: 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 ...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.
全体 : Cryo-EM structure of afamelanotide-bound melanocortin-1 receptor ...
全体
名称: Cryo-EM structure of afamelanotide-bound melanocortin-1 receptor in complex with Gs protein and scFv16
要素
複合体: Cryo-EM structure of afamelanotide-bound melanocortin-1 receptor in complex with Gs protein and scFv16
複合体: scFv16
タンパク質・ペプチド: scFv16
複合体: Melanocortin-1 receptor
タンパク質・ペプチド: Melanocortin-1 receptor
複合体: Guanine nucleotide-binding protein G(i) subunit alpha-1
タンパク質・ペプチド: Guanine nucleotide-binding protein G(i) subunit alpha-1
複合体: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
タンパク質・ペプチド: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
複合体: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
タンパク質・ペプチド: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
複合体: Afamelanotide
タンパク質・ペプチド: Afamelanotide
リガンド: CALCIUM ION
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超分子 #1: Cryo-EM structure of afamelanotide-bound melanocortin-1 receptor ...
超分子
名称: Cryo-EM structure of afamelanotide-bound melanocortin-1 receptor in complex with Gs protein and scFv16 タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: #1-#6