8E3X

Cryo-EM structure of the PAC1R-PACAP27-Gs complex

8E3X の概要

• エントリーDOI: 10.2210/pdb8e3x/pdb
• EMDBエントリー: 27872
• 分子名称: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (7 entities in total)
• 機能のキーワード: membrane protein, drug discovery, g protein coupled receptor, signalling
• 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: 165813.23

構造登録者

Piper, S.J.,Danev, R.,Sexton, P.,Wootten, D. (登録日: 2022-08-17, 公開日: 2022-11-23, 最終更新日: 2025-05-14)

主引用文献

Piper, S.J.,Deganutti, G.,Lu, J.,Zhao, P.,Liang, Y.L.,Lu, Y.,Fletcher, M.M.,Hossain, M.A.,Christopoulos, A.,Reynolds, C.A.,Danev, R.,Sexton, P.M.,Wootten, D.
Understanding VPAC receptor family peptide binding and selectivity.
Nat Commun, 13:7013-7013, 2022

PubMed Abstract: The vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) receptors are key regulators of neurological processes. Despite recent structural data, a comprehensive understanding of peptide binding and selectivity among different subfamily receptors is lacking. Here, we determine structures of active, Gs-coupled, VIP-VPAC1R, PACAP27-VPAC1R, and PACAP27-PAC1R complexes. Cryo-EM structural analyses and molecular dynamics simulations (MDSs) reveal fewer stable interactions between VPAC1R and VIP than for PACAP27, more extensive dynamics of VIP interaction with extracellular loop 3, and receptor-dependent differences in interactions of conserved N-terminal peptide residues with the receptor core. MD of VIP modelled into PAC1R predicts more transient VIP-PAC1R interactions in the receptor core, compared to VIP-VPAC1R, which may underlie the selectivity of VIP for VPAC1R over PAC1R. Collectively, our work improves molecular understanding of peptide engagement with the PAC1R and VPAC1R that may benefit the development of novel selective agonists.

PubMed: 36385145
DOI: 10.1038/s41467-022-34629-3

実験手法

ELECTRON MICROSCOPY (2.3 Å)