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Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators 期刊论文 WOS高被引论文

编号：

46fbd37b-4073-40a5-985a-4324f979aebe
作者：

Song, Gaojie^[1] Yang, Dehua^[2,3] Wang, Yuxia^[1] de Graaf, Chris^[4] Zhou, Qingtong^[1] Jiang, Shanshan^[5] Liu, Kaiwen^[1,6,7] Cai, Xiaoqing^[2,3] Dai, Antao^[2,3] Lin, Guangyao^[6] Liu, Dongsheng^[1] Wu, Fan^[1,6,7] Wu, Yiran^[1] Zhao, Suwen^[1,6] Ye, Li^[5] Han, Gye Won^[8] Lau, Jesper^[9] Wu, Beili^[6,7,10] Hanson, Michael A.^[11] Liu, ZhiJie^[1,6,12] Wang, MingWei^[2,3,5,6] Stevens, Raymond C.^[1,6]
语种：

英文
期刊：

NATURE ISSN：0028-0836 2017 年 546 卷 7657 期 (312 - +) ; JUN 8
收录：
摘要：

The glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCGR) are members of the secretin-like class B family of G-protein-coupled receptors (GPCRs) and have opposing physiological roles in insulin release and glucose homeostasis(1). The treatment of type 2 diabetes requires positive modulation of GLP-1R to inhibit glucagon secretion and stimulate insulin secretion in a glucose-dependent manner(2). Here we report crystal structures of the human GLP-1R transmembrane domain in complex with two different negative allosteric modulators, PF-06372222 and NNC0640, at 2.7 and 3.0 angstrom resolution, respectively. The structures reveal a common binding pocket for negative allosteric modulators, present in both GLP-1R and GCGR(3) and located outside helices V-VII near the intracellular half of the receptor. The receptor is in an inactive conformation with compounds that restrict movement of the intracellular tip of helix VI, a movement that is generally associated with activation mechanisms in class A GPCRs(4-6). Molecular modelling and mutagenesis studies indicate that agonist positive allosteric modulators target the same general region, but in a distinct sub-pocket at the interface between helices V and VI, which may facilitate the formation of an intracellular binding site that enhances G-protein coupling.
推荐引用方式
GB/T 7714：

Song Gaojie,Yang Dehua,Wang Yuxia, et al. Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators [J].NATURE,2017,546(7657):312-+.
APA：

Song Gaojie,Yang Dehua,Wang Yuxia,de Graaf Chris,&Stevens Raymond C..(2017).Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators .NATURE,546(7657):312-+.
MLA：

Song Gaojie, et al. "Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators" .NATURE 546,7657(2017):312-+.
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