Structural basis for GPR40 allosteric agonism and incretin stimulation.

ABSTRACT: Activation of free fatty acid receptor 1 (GPR40) by synthetic partial and full agonists occur via distinct allosteric sites. A crystal structure of GPR40-TAK-875 complex revealed the allosteric site for the partial agonist. Here we report the 2.76-Å crystal structure of human GPR40 in complex with a synthetic full agonist, compound 1, bound to the second allosteric site. Unlike TAK-875, which acts as a Gα_q-coupled partial agonist, compound 1 is a dual Gα_q and Gα_s-coupled full agonist. compound 1 binds in the lipid-rich region of the receptor near intracellular loop 2 (ICL2), in which the stabilization of ICL2 by the ligand is likely the primary mechanism for the enhanced G protein activities. The endogenous free fatty acid (FFA), γ-linolenic acid, can be co

SUBMITTER: Ho JD 

PROVIDER: S-EPMC5917010 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature