8RVW
Dark structure of the human adenosine A2A receptor bound to synthetic photoswitch "StilSwitch3" determined by serial synchrotron crystallography
This is a non-PDB format compatible entry.
Summary for 8RVW
| Entry DOI | 10.2210/pdb8rvw/pdb |
| Descriptor | 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) |
| Functional Keywords | gpcr, adenosine receptor, synthetic photoswitch, parkinson's disease, membrane protein |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 1 |
| Total formula weight | 57031.61 |
| Authors | |
| Primary citation | 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 Cited by 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: 39738009DOI: 10.1038/s41467-024-55109-w PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.65 Å) |
Structure validation
Download full validation report
