Delineating the activation mechanism and conformational landscape of a class B G protein-coupled receptor glucagon receptor.

ABSTRACT: Class B G protein-coupled receptors (GPCRs) are important targets in the treatment of metabolic syndrome and diabetes. Although multiple structures of class B GPCRs-G protein complexes have been elucidated, the detailed activation mechanism of the receptors remains unclear. Here, we combine Gaussian accelerated molecular dynamics simulations and Markov state models (MSM) to investigate the activation mechanism of a canonical class B GPCR, human glucagon receptor-GCGR, including the negative allosteric modulator-bound inactive state, the agonist glucagon-bound active state, and both glucagon- and Gs-bound fully active state. The free-energy landscapes of GCGR show the conformational ensemble consisting of three activation-associated states: inactive, active, and fully active. The structural

SUBMITTER: Wang Y 

PROVIDER: S-EPMC8801358 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature