Domain coupling in activation of a family C GPCR.

ABSTRACT: The G protein-coupled metabotropic glutamate receptors form homodimers and heterodimers with highly diverse responses to glutamate and varying physiological functions. We employ molecular dynamics, single-molecule spectroscopy and hydrogen-deuterium exchange to dissect the activation pathway triggered by glutamate. We find that activation entails multiple loosely coupled steps, including formation of an agonist-bound, pre-active intermediate whose transition to active conformations forms dimerization interface contacts that set efficacy. The agonist-bound receptor populates at least two additional intermediates en route to G protein-coupling conformations. Sequential transitions into these states act as 'gates', which attenuate the effects of glutamate. Thus, the agonist-bound receptor is

SUBMITTER: Latorraca NR 

PROVIDER: S-EPMC12394075 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature