Molecular dynamics-guided discovery of an ago-allosteric modulator for GPR40/FFAR1.

ABSTRACT: The long-chain fatty acid receptor FFAR1/GPR40 binds agonists in both an interhelical site between the extracellular segments of transmembrane helix (TM)-III and TM-IV and a lipid-exposed groove between the intracellular segments of these helices. Molecular dynamics simulations of FFAR1 with agonist removed demonstrated a major rearrangement of the polar and charged anchor point residues for the carboxylic acid moiety of the agonist in the interhelical site, which was associated with closure of a neighboring, solvent-exposed pocket between the extracellular poles of TM-I, TM-II, and TM-VII. A synthetic compound designed to bind in this pocket, and thereby prevent its closure, was identified through structure-based virtual screening and shown to function both as an agonist and as an alloste

SUBMITTER: Luckmann M 

PROVIDER: S-EPMC6452680 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature