Structural Connection between Activation Microswitch and Allosteric Sodium Site in GPCR Signaling.

ABSTRACT: Sodium ions are endogenous allosteric modulators of many G-protein-coupled receptors (GPCRs). Mutation of key residues in the sodium binding motif causes a striking effect on G-protein signaling. We report the crystal structures of agonist complexes for two variants in the first sodium coordination shell of the human A_2A adenosine receptor, D52^2.50N and S91^3.39A. Both structures present an overall active-like conformation; however, the variants show key changes in the activation motif NPxxY. Changes in the hydrogen bonding network in this microswitch suggest a possible mechanism for modified G-protein signaling and enhanced thermal stability. These structures, signaling data, and thermal stability analysis with a panel of pharmacological ligands provide a b

SUBMITTER: White KL 

PROVIDER: S-EPMC5810373 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature