Structural basis for GPR40 allosteric agonism and incretin stimulation.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 29695780.
- Also identified by DOI 10.1038/s41467-017-01240-w and PMC identifier 5917010.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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<sub>q</sub>-coupled partial agonist, compound 1 is a dual Gα<sub>q</sub> and Gα<sub>s</sub>-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 computationally modeled in this site. Both γ-linolenic acid and compound 1 exhibit positive cooperativity with TAK-875, suggesting that this site could also serve as a FFA binding site.
Medical subject headings
- Diabetes Mellitus, Type 2
- Hypoglycemic Agents
- Incretins
- Insulin Secretion
- Receptors, G-Protein-Coupled