Structural basis for GPR40 allosteric agonism and incretin stimulation.
Structural basis for GPR40 allosteric agonism and incretin stimulation.
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DOI：
10.1038/s41467-017-01240-w
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发表时间：
2018-04-25
影响因子：
16.6
通讯作者：
Hamdouchi C
中科院分区：
文献类型：
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作者：
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-Rafizadeh C;Genin MJ;Miller AR;Hamdouchi C
合成的部分和完全激动剂激活游离脂肪酸受体1 （GPR40）通过不同的变构位点发生。GPR40-TAK-875配合物的晶体结构揭示了部分激动剂的变构位点。在这里，我们报道了人类GPR40的2.76-Å晶体结构与合成的完全激动剂化合物1结合在第二个变构位点。与TAK-875作为Gαq偶联部分激动剂不同，化合物1是Gαq和g αs偶联的完全激动剂。化合物1结合在细胞内环2 （ICL2）附近受体的富脂区，其中配体对ICL2的稳定可能是G蛋白活性增强的主要机制。内源性游离脂肪酸(FFA) γ-亚麻酸可以在该位点进行计算建模。γ-亚麻酸和化合物1均与TAK-875表现出正的协同作用，表明该位点也可能作为FFA结合位点。GPR40是一种g蛋白偶联受体，与游离脂肪酸结合，介导胰岛素和肠促胰岛素分泌。在这里，作者展示了人类GPR40的晶体结构，其激动剂与位于富脂区附近的变构位点结合，这表明了偏向激动作用的机制。
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. GPR40 is a G-protein coupled receptor that binds to free fatty acids, mediating insulin and incretin secretion. Here, the authors present the crystal structure of human GPR40 with an agonist bound to an allosteric site located near the lipid-rich region that suggests a mechanism for biased agonism.
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DOI：
10.1107/s0907444905036693
发表时间：
2006-01-01
影响因子：
2.2
作者：
Evans, P
通讯作者：
Evans, P
一类强效 GPR40 完全激动剂可作用于肠岛轴，促进啮齿类动物的血糖控制。
影响因子：
3.7
作者：
Luo J;Swaminath G;Brown SP;Zhang J;Guo Q;Chen M;Nguyen K;Tran T;Miao L;Dransfield PJ;Vimolratana M;Houze JB;Wong S;Toteva M;Shan B;Li F;Zhuang R;Lin DC
通讯作者：
Lin DC
影响因子：
56.9
作者：
CONNOLLY, ML
通讯作者：
CONNOLLY, ML
影响因子：
3.5
作者：
GERBER, PR;MULLER, K
通讯作者：
MULLER, K
影响因子：
14.8
作者：
通讯作者：
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