Identification of ligand-specific G protein-coupled receptor states and prediction of downstream efficacy via data-driven modeling.

ABSTRACT: Ligand binding stabilizes different G protein-coupled receptor states via a complex allosteric process that is not completely understood. Here, we have derived free energy landscapes describing activation of the β₂ adrenergic receptor bound to ligands with different efficacy profiles using enhanced sampling molecular dynamics simulations. These reveal shifts toward active-like states at the Gprotein-binding site for receptors bound to partial and full agonists, and that the ligands modulate the conformational ensemble of the receptor by tuning protein microswitches. We indeed find an excellent correlation between the conformation of the microswitches close to the ligand binding site and in the transmembrane region and experimentally reported cyclic adenosine monophosphate signal

SUBMITTER: Fleetwood O 

PROVIDER: S-EPMC7886328 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature