Deciphering conformational selectivity in the A2A adenosine G protein-coupled receptor by free energy simulations.

ABSTRACT: Transmembranal G Protein-Coupled Receptors (GPCRs) transduce extracellular chemical signals to the cell, via conformational change from a resting (inactive) to an active (canonically bound to a G-protein) conformation. Receptor activation is normally modulated by extracellular ligand binding, but mutations in the receptor can also shift this equilibrium by stabilizing different conformational states. In this work, we built structure-energetic relationships of receptor activation based on original thermodynamic cycles that represent the conformational equilibrium of the prototypical A2A adenosine receptor (AR). These cycles were solved with efficient free energy perturbation (FEP) protocols, allowing to distinguish the pharmacological profile of different series of A2AAR agonists with diffe

SUBMITTER: Jespers W 

PROVIDER: S-EPMC8654218 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature