7F4D

Cryo-EM structure of alpha-MSH-bound melanocortin-1 receptor in complex with Gs protein and Nb35

7F4D の概要

• エントリーDOI: 10.2210/pdb7f4d/pdb
• EMDBエントリー: 31448 31449 31452 31453
• 分子名称: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, Guanine nucleotide-binding protein G(i) subunit alpha-1, Nanobody 35, ... (7 entities in total)
• 機能のキーワード: g protein-coupled receptors, melanocyte, clacium ion, activation, membrane protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 177157.06

構造登録者

Ma, S.,Chen, Y.,Dai, A.,Yin, W.,Guo, J.,Yang, D.,Zhou, F.,Jiang, Y.,Wang, M.-W.,Xu, H.E. (登録日: 2021-06-18, 公開日: 2021-09-08, 最終更新日: 2024-10-23)

主引用文献

Ma, S.,Chen, Y.,Dai, A.,Yin, W.,Guo, J.,Yang, D.,Zhou, F.,Jiang, Y.,Wang, M.W.,Xu, H.E.
Structural mechanism of calcium-mediated hormone recognition and G beta interaction by the human melanocortin-1 receptor.
Cell Res., 31:1061-1071, 2021

PubMed Abstract: 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.

PubMed: 34453129
DOI: 10.1038/s41422-021-00557-y

実験手法

ELECTRON MICROSCOPY (3 Å)