G蛋白偶联受体
速激肽受体1
P物质
受体
细胞生物学
细胞外
信号转导
神经肽
G蛋白
Gqα亚单位
神经激肽A
化学
神经激肽B
生物
生物物理学
作者
J.A. Harris,Bryan Faust,Arisbel B. Gondin,Marc A. Dämgen,Carl‐Mikael Suomivuori,Nicholas A. Veldhuis,Yifan Cheng,Ron O. Dror,David M. Thal,Aashish Manglik
标识
DOI:10.1038/s41589-021-00890-8
摘要
The neuropeptide substance P (SP) is important in pain and inflammation. SP activates the neurokinin-1 receptor (NK1R) to signal via Gq and Gs proteins. Neurokinin A also activates NK1R, but leads to selective Gq signaling. How two stimuli yield distinct G protein signaling at the same G protein-coupled receptor remains unclear. We determined cryogenic-electron microscopy structures of active NK1R bound to SP or the Gq-biased peptide SP6-11. Peptide interactions deep within NK1R are critical for receptor activation. Conversely, interactions between SP and NK1R extracellular loops are required for potent Gs signaling but not Gq signaling. Molecular dynamics simulations showed that these superficial contacts restrict SP flexibility. SP6-11, which lacks these interactions, is dynamic while bound to NK1R. Structural dynamics of NK1R agonists therefore depend on interactions with the receptor extracellular loops and regulate G protein signaling selectivity. Similar interactions between other neuropeptides and their cognate receptors may tune intracellular signaling.
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