Conformational Transitions of the Pituitary Adenylate Cyclase-Activating Polypeptide Receptor, a Human Class B GPCR.

ABSTRACT: The G protein-coupled pituitary adenylate cyclase-activating polypeptide receptor (PAC1R) is a potential therapeutic target for endocrine, metabolic and stress-related disorders. However, many questions regarding the protein structure and dynamics of PAC1R remain largely unanswered. Using microsecond-long simulations, we examined the open and closed PAC1R conformations interconnected within an ensemble of transitional states. The open-to-closed transition can be initiated by "unzipping" the extracellular domain and the transmembrane domain, mediated by a unique segment within the ?3-?4 loop. Transitions between different conformational states range between microseconds to milliseconds, which clearly implicate allosteric effects propagating from the extracellular face of the receptor to the intracellular G protein-binding site. Such allosteric dynamics provides structural and mechanistic insights for the activation and modulation of PAC1R and related class B receptors.

SUBMITTER: Liao C 

PROVIDER: S-EPMC5511175 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature