Minute-timescale free-energy calculations reveal a pseudo-active state in the adenosine A_2A receptor activation mechanism.

ABSTRACT: G protein-coupled receptors (GPCRs) are membrane proteins targeted by over one-third of marketed drugs. Understanding their activation mechanism is essential for precise regulation of drug pharmacological response. In this work, we elucidate the conformational landscape of the adenosine A_2A receptor (A_2AR) activation mechanism in its basal apo form and under different ligand-bound conditions through minute-timescale free-energy calculations. We identified a pseudo-active state (pAs) of the A_2AR apo form, stabilized by specific "microswitch" residues, including a salt bridge established between the conserved residues R^5.66 and E^6.30. The pAs enables A_2AR to couple with Gs protein upon rearrangement of the intracellular

SUBMITTER: D'Amore VM 

PROVIDER: S-EPMC11965979 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature