Lilly Biotechnology Center San Diego, 10290 Campus Point Drive, San Diego, CA, 92121, USA.
Lilly Research Laboratories, Lilly Corporate Center, 355 East Merrill Street, Indianapolis, IN, 46285, USA.
Nat Commun. 2018 Apr 25;9(1):1645. doi: 10.1038/s41467-017-01240-w.
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 Gα-coupled partial agonist, compound 1 is a dual Gα and Gα-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.
游离脂肪酸受体 1（GPR40）的合成部分和完全激动剂的激活是通过不同的变构位点发生的。GPR40-TAK-875 复合物的晶体结构揭示了部分激动剂的变构位点。在这里，我们报告了人 GPR40 与合成完全激动剂化合物 1 复合物的 2.76Å 晶体结构，该化合物结合在第二个变构位点上。与作为 Gα 偶联部分激动剂的 TAK-875 不同，化合物 1 是一种双重 Gα 和 Gα 偶联的完全激动剂。化合物 1 结合在受体的富含脂质区域，靠近细胞内环 2（ICL2），配体稳定 ICL2 可能是增强 G 蛋白活性的主要机制。内源性游离脂肪酸（FFA）γ-亚麻酸可以在该部位进行计算建模。γ-亚麻酸和化合物 1 都与 TAK-875 表现出正协同作用，这表明该部位也可以作为 FFA 结合位点。
