8RVW

Dark structure of the human adenosine A2A receptor bound to synthetic photoswitch "StilSwitch3" determined by serial synchrotron crystallography

これはPDB形式変換不可エントリーです。

8RVW の概要

• エントリーDOI: 10.2210/pdb8rvw/pdb
• 分子名称: Adenosine receptor A2a,Adenosine receptor A2a,Soluble cytochrome b562, OLEIC ACID, 1,3-diethyl-8-[(~{E})-2-(4-methoxy-3-oxidanyl-phenyl)ethenyl]-7-methyl-purine-2,6-dione, ... (6 entities in total)
• 機能のキーワード: gpcr, adenosine receptor, synthetic photoswitch, parkinson's disease, 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: 57031.61

構造登録者

Glover, H.,Bertrand, Q. (登録日: 2024-02-02, 公開日: 2025-01-08)

主引用文献

Glover, H.,Sassmannshausen, T.,Bertrand, Q.,Trabuco, M.,Slavov, C.,Bacchin, A.,Andres, F.,Kondo, Y.,Stipp, R.,Wranik, M.,Khusainov, G.,Carrillo, M.,Kekilli, D.,Nan, J.,Gonzalez, A.,Cheng, R.,Neidhart, W.,Weinert, T.,Leonarski, F.,Dworkowski, F.,Kepa, M.,Wachtveitl, J.,Hennig, M.,Standfuss, J.
Photoswitch dissociation from a G protein-coupled receptor resolved by time-resolved serial crystallography.
Nat Commun, 15:10837-10837, 2024

PubMed Abstract: G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors in humans. The binding and dissociation of ligands tunes the inherent conformational flexibility of these important drug targets towards distinct functional states. Here we show how to trigger and resolve protein-ligand interaction dynamics within the human adenosine A receptor. For this, we designed seven photochemical affinity switches derived from the anti-Parkinson's drug istradefylline. In a rational approach based on UV/Vis spectroscopy, time-resolved absorption spectroscopy, differential scanning fluorimetry and cryo-crystallography, we identified compounds suitable for time-resolved serial crystallography. Our analysis of millisecond-scale dynamics revealed how trans-to-cis isomerization shifts selected istradefylline derivatives within the binding pocket. Depending on the chemical nature of the ligand, interactions between extracellular loops 2 and 3, acting as a lid on the binding pocket, are disrupted and rearrangement of the orthosteric binding pocket is invoked upon ligand dissociation. This innovative approach provides insights into GPCR dynamics at the atomic level, offering potential for developing novel pharmaceuticals.

PubMed: 39738009
DOI: 10.1038/s41467-024-55109-w

実験手法

X-RAY DIFFRACTION (2.65 Å)