7RMI

SP6-11 biased agonist bound to active human neurokinin 1 receptor in complex with miniGs/q70

7RMI の概要

• エントリーDOI: 10.2210/pdb7rmi/pdb
• EMDBエントリー: 24572
• 分子名称: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, with certain residues mutated to match Guanine nucleotide-binding protein G(q) subunit, Substance-P receptor, Substance P 6-11, ... (6 entities in total)
• 機能のキーワード: substance p, g protein, gpcr, neurokinin, tachykinin, signaling protein, signaling protein-membrane protein complex, signaling protein/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: 138482.12

構造登録者

Harris, J.A.,Faust, B.,Gondin, A.B.,Daemgen, M.A.,Suomivuori, C.M.,Veldhuis, N.A.,Cheng, Y.,Dror, R.O.,Thal, D.,Manglik, A. (登録日: 2021-07-27, 公開日: 2021-11-03, 最終更新日: 2024-11-13)

主引用文献

Harris, J.A.,Faust, B.,Gondin, A.B.,Damgen, M.A.,Suomivuori, C.M.,Veldhuis, N.A.,Cheng, Y.,Dror, R.O.,Thal, D.M.,Manglik, A.
Selective G protein signaling driven by substance P-neurokinin receptor dynamics.
Nat.Chem.Biol., 18:109-115, 2022

PubMed Abstract: The neuropeptide substance P (SP) is important in pain and inflammation. SP activates the neurokinin-1 receptor (NK1R) to signal via G and G proteins. Neurokinin A also activates NK1R, but leads to selective G 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 G-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 G signaling but not G 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.

PubMed: 34711980
DOI: 10.1038/s41589-021-00890-8

実験手法

ELECTRON MICROSCOPY (3.2 Å)