Activation pathway of a G protein-coupled receptor uncovers conformational intermediates as targets for allosteric drug design.

ABSTRACT: G protein-coupled receptors (GPCRs) are the most common proteins targeted by approved drugs. A complete mechanistic elucidation of large-scale conformational transitions underlying the activation mechanisms of GPCRs is of critical importance for therapeutic drug development. Here, we apply a combined computational and experimental framework integrating extensive molecular dynamics simulations, Markov state models, site-directed mutagenesis, and conformational biosensors to investigate the conformational landscape of the angiotensin II (AngII) type 1 receptor (AT₁ receptor) - a prototypical class A GPCR-activation. Our findings suggest a synergistic transition mechanism for AT₁ receptor activation. A key intermediate state is identified in the activation pathway, which

SUBMITTER: Lu S 

PROVIDER: S-EPMC8342441 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature