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- Title
Structural basis for GPR40 allosteric agonism and incretin stimulation.
- Authors
Ho, Joseph D.; Chau, Betty; Rodgers, Logan; Lu, Frances; Wilbur, Kelly L.; Otto, Keith A.; Yanyun Chen; Min Song; Riley, Jonathan P.; Hsiu-Chiung Yang; Reynolds, Nichole A.; Kahl, Steven D.; Lewis, Anjana Patel; Groshong, Christopher; Madsen, Russell E.; Conners, Kris; Lineswala, Jayana P.; Gheyi, Tarun; Decipulo Saflor, Melbert-Brian; Lee, Matthew R.
- 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 Gαq-coupled partial agonist, compound 1 is a dual Gαq and Gαs-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.
- Subjects
FREE fatty acids; CYCLOSERINE; G proteins; CRYSTAL structure; BINDING sites
- Publication
Nature Communications, 2018, Vol 9, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-017-01240-w