8U8F

GPR3 Orphan G-coupled Protein Receptor in complex with Dominant Negative Gs.

8U8F の概要

• エントリーDOI: 10.2210/pdb8u8f/pdb
• EMDBエントリー: 42023
• 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, ... (5 entities in total)
• 機能のキーワード: gpr3, orphan gpcr, gpcr, membrane protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 131533.92

構造登録者

Russell, I.C.,Belousoff, M.J.,Sexton, P. (登録日: 2023-09-17, 公開日: 2024-03-06, 最終更新日: 2025-05-21)

主引用文献

Russell, I.C.,Zhang, X.,Bumbak, F.,McNeill, S.M.,Josephs, T.M.,Leeming, M.G.,Christopoulos, G.,Venugopal, H.,Flocco, M.M.,Sexton, P.M.,Wootten, D.,Belousoff, M.J.
Lipid-Dependent Activation of the Orphan G Protein-Coupled Receptor, GPR3.
Biochemistry, 63:625-631, 2024

PubMed Abstract: The class A orphan G protein-coupled receptor (GPCR), GPR3, has been implicated in a variety of conditions, including Alzheimer's and premature ovarian failure. GPR3 constitutively couples with Gαs, resulting in the production of cAMP in cells. While tool compounds and several putative endogenous ligands have emerged for the receptor, its endogenous ligand, if it exists, remains a mystery. As novel potential drug targets, the structures of orphan GPCRs have been of increasing interest, revealing distinct modes of activation, including autoactivation, presence of constitutively activating mutations, or via cryptic ligands. Here, we present a cryo-electron microscopy (cryo-EM) structure of the orphan GPCR, GPR3 in complex with DNGαs and Gβγ. The structure revealed clear density for a lipid-like ligand that bound within an extended hydrophobic groove, suggesting that the observed "constitutive activity" was likely due to activation via a lipid that may be ubiquitously present. Analysis of conformational variance within the cryo-EM data set revealed twisting motions of the GPR3 transmembrane helices that appeared coordinated with changes in the lipid-like density. We propose a mechanism for the binding of a lipid to its putative orthosteric binding pocket linked to the GPR3 dynamics.

PubMed: 38376112
DOI: 10.1021/acs.biochem.3c00647

実験手法

ELECTRON MICROSCOPY (3.49 Å)