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.
journal_name
Nat Communjournal_title
Nature communicationsauthors
Ho JD,Chau B,Rodgers L,Lu F,Wilbur KL,Otto KA,Chen Y,Song M,Riley JP,Yang HC,Reynolds NA,Kahl SD,Lewis AP,Groshong C,Madsen RE,Conners K,Lineswala JP,Gheyi T,Saflor MD,Lee MR,Benach J,Baker KA,Montrose-Rafizaddoi
10.1038/s41467-017-01240-wsubject
Has Abstractpub_date
2018-04-25 00:00:00pages
1645issue
1issn
2041-1723pii
10.1038/s41467-017-01240-wjournal_volume
9pub_type
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