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摘要 : 美国加州结构生物学和核心科学与技术部门的研究人员在近日的一项研究中,报告了与TAK-875 形成复合物的hGPR40的详细原子结构。相关文章发表于2014年7月20日的《Nature》杂志上。

“G-蛋白耦合受体”(GPCR) “人GPR40” (hGPR40,亦称为“自由脂肪酸受体-1”)是用于2-型糖尿病治疗的一个有吸引力的治疗目标。它是一种膜蛋白,主要是在胰腺 β-细胞中和小肠肠内分泌细胞中表达,充当一个营养物传感器,增强胰岛素分泌和“胰高血糖素样受体-1”的分泌。

这项研究报告了与TAK-875 (fasiglifam,它是GPR40 的一个部分激动剂,目前正在进行三期临床试验)形成复合物的hGPR40的详细原子结构。该结构显示TAK-875以一种通常的方式结合,并且表明TAK-875和天然基质通过脂质双层进入“受体结合袋”。


High-resolution structure of the human GPR40 receptor bound to allosteric agonist TAK-875

Ankita Srivastava, Jason Yano, Yoshihiko Hirozane, Georgia Kefala, Franz Gruswitz,Gyorgy Snell, Weston Lane, Anthony Ivetac, Kathleen Aertgeerts, Jasmine Nguyen, Andy Jennings & Kengo Okada

Human GPR40 receptor (hGPR40), also known as free fatty-acid receptor 1 (FFAR1), is a G-protein-coupled receptor that binds long-chain free fatty acids to enhance glucose-dependent insulin secretion. Novel treatments for type-2 diabetes mellitus are therefore possible by targeting hGPR40 with partial or full agonists. TAK-875, or fasiglifam, is an orally available, potent and selecive partial agonist of hGPR40 receptor, which reached phase III clinical trials for the potential treatment of type-2 diabetes mellitus. Data from clinical studies indicate that TAK-875, which is an ago-allosteric modulator of hGPR40 (ref. 3), demonstrates improved glycaemic control and low hypoglycaemic risk in diabetic patients. Here we report the crystal structure of hGPR40 receptor bound to TAK-875 at 2.3 Å resolution. The co-complex structure reveals a unique binding mode of TAK-875 and suggests that entry to the non-canonical binding pocket most probably occurs via the lipid bilayer. The atomic details of the extensive charge network in the ligand binding pocket reveal additional interactions not identified in previous studies and contribute to a clear understanding of TAK-875 binding to the receptor. The hGPR40–TAK-875 structure also provides insights into the plausible binding of multiple ligands to the receptor, which has been observed in radioligand binding and Ca2+ influx assay studies. Comparison of the transmembrane helix architecture with other G-protein-coupled receptors suggests that the crystallized TAK-875-bound hGPR40 complex is in an inactive-like state.

对应Nature杂志: 2014年9月4日Nature杂志精选

来源: Nature 浏览次数:151


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