8S4D

Crystal structure of a peptidergic GPCR in complex with a small synthetic G protein-biased agonist

これはPDB形式変換不可エントリーです。

8S4D の概要

• エントリーDOI: 10.2210/pdb8s4d/pdb
• 分子名称: Apelin receptor,Soluble cytochrome b562, (3~{S})-5-methyl-3-[[1-pentan-3-yl-2-(thiophen-2-ylmethyl)benzimidazol-5-yl]carbonylamino]hexanoic acid, OLEIC ACID, ... (5 entities in total)
• 機能のキーワード: receptor, gpcr, stabilised, membrane protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 58646.47

構造登録者

Verdon, G.,Currinn, H.,Solcan, N.,Schlenker, O.,Brown, A.J.H. (登録日: 2024-02-21, 公開日: 2024-12-04, 最終更新日: 2025-01-22)

主引用文献

Williams, T.L.,Verdon, G.,Kuc, R.E.,Currinn, H.,Bender, B.,Solcan, N.,Schlenker, O.,Macrae, R.G.C.,Brown, J.,Schutz, M.,Zhukov, A.,Sinha, S.,de Graaf, C.,Graf, S.,Maguire, J.J.,Brown, A.J.H.,Davenport, A.P.
Structural and functional determination of peptide versus small molecule ligand binding at the apelin receptor.
Nat Commun, 15:10714-10714, 2024

PubMed Abstract: We describe a structural and functional study of the G protein-coupled apelin receptor, which binds two endogenous peptide ligands, apelin and Elabela/Toddler (ELA), to regulate cardiovascular development and function. Characterisation of naturally occurring apelin receptor variants from the UK Genomics England 100,000 Genomes Project, and AlphaFold2 modelling, identifies T89 as important in the ELA binding site, and R168 as forming extensive interactions with the C-termini of both peptides. Base editing to introduce an R/H168 variant into human stem cell-derived cardiomyocytes demonstrates that this residue is critical for receptor binding and function. Additionally, we present an apelin receptor crystal structure bound to the G protein-biased, small molecule agonist, CMF-019, which reveals a deeper binding mode versus the endogenous peptides at lipophilic pockets between transmembrane helices associated with GPCR activation. Overall, the data provide proof-of-principle for using genetic variation to identify key sites regulating receptor-ligand engagement.

PubMed: 39730334
DOI: 10.1038/s41467-024-55381-w

実験手法

X-RAY DIFFRACTION (2.584 Å)