| First Author | Ho JD | Year | 2018 |
| Journal | Nat Commun | Volume | 9 |
| Issue | 1 | Pages | 1645 |
| PubMed ID | 29695780 | Mgi Jnum | J:265430 |
| Mgi Id | MGI:6158230 | Doi | 10.1038/s41467-017-01240-w |
| Citation | Ho JD, et al. (2018) Structural basis for GPR40 allosteric agonism and incretin stimulation. Nat Commun 9(1):1645 |
| abstractText | 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-A 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 Galphaq-coupled partial agonist, compound 1 is a dual Galphaq and Galphas-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), gamma-linolenic acid, can be computationally modeled in this site. Both gamma-linolenic acid and compound 1 exhibit positive cooperativity with TAK-875, suggesting that this site could also serve as a FFA binding site. |
