期刊
NATURE COMMUNICATIONS
卷 9, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-017-01240-w
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资金
- DOE Office of Science by Argonne National Laboratory [DE-AC02-06CH11357]
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 Gaq-coupled partial agonist, compound 1 is a dual Gaq and Gas-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.
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