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Nat Commun. 2018 Apr 25;9(1):1645. doi: 10.1038/s41467-017-01240-w.

Structural basis for GPR40 allosteric agonism and incretin stimulation.

Author information

1
Lilly Biotechnology Center San Diego, 10290 Campus Point Drive, San Diego, CA, 92121, USA. ho_joseph_d@lilly.com.
2
Lilly Biotechnology Center San Diego, 10290 Campus Point Drive, San Diego, CA, 92121, USA.
3
Lilly Research Laboratories, Lilly Corporate Center, 355 East Merrill Street, Indianapolis, IN, 46285, USA.
4
Lilly Research Laboratories Collaborative Access Team, Advanced Photon Source, Argonne National Laboratory, Building 438A, 9700 S. Cass Avenue, Lemont, IL, 60439, USA.
5
Lilly Research Laboratories, Lilly Corporate Center, 355 East Merrill Street, Indianapolis, IN, 46285, USA. hamdouchi_chafiq@lilly.com.

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.

PMID:
29695780
PMCID:
PMC5917010
DOI:
10.1038/s41467-017-01240-w
[Indexed for MEDLINE]
Free PMC Article

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