Intermediate-state-trapped mutants pinpoint G protein-coupled receptor conformational allostery.

ABSTRACT: Understanding the roles of intermediate states in signaling is pivotal to unraveling the activation processes of G protein-coupled receptors (GPCRs). However, the field is still struggling to define these conformational states with sufficient resolution to study their individual functions. Here, we demonstrate the feasibility of enriching the populations of discrete states via conformation-biased mutants. These mutants adopt distinct distributions among five states that lie along the activation pathway of adenosine A_2A receptor (A_2AR), a class A GPCR. Our study reveals a structurally conserved cation-π lock between transmembrane helix VI (TM6) and Helix8 that regulates cytoplasmic cavity opening as a "gatekeeper" for G protein penetration. A GPCR activation process ba

SUBMITTER: Wang X 

PROVIDER: S-EPMC10006191 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature