Mechanistic insights into allosteric regulation of the A_2A adenosine G protein-coupled receptor by physiological cations.

ABSTRACT: Cations play key roles in regulating G-protein-coupled receptors (GPCRs), although their mechanisms are poorly understood. Here, ¹⁹F NMR is used to delineate the effects of cations on functional states of the adenosine A_2A GPCR. While Na⁺ reinforces an inactive ensemble and a partial-agonist stabilized state, Ca²⁺ and Mg²⁺ shift the equilibrium toward active states. Positive allosteric effects of divalent cations are more pronounced with agonist and a G-protein-derived peptide. In cell membranes, divalent cations enhance both the affinity and fraction of the high affinity agonist-bound state. Molecular dynamics simulations suggest high concentrations of divalent cations bridge specific extracellular acidic residues, bringing TM5 and TM

SUBMITTER: Ye L 

PROVIDER: S-EPMC5893540 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature