Photoswitch dissociation from a G protein-coupled receptor resolved by time-resolved serial crystallography.

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_2A 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 isomerizati

SUBMITTER: Glover H 

PROVIDER: S-EPMC11686364 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature