High-resolution structure of the human GPR40 receptor bound to allosteric agonist TAK-875
High-resolution structure of the human GPR40 receptor bound to allosteric agonist TAK-875
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DOI：
10.1038/nature13494
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发表时间：
2014-09-04
期刊：
影响因子：
64.8
通讯作者：
Okada, Kengo
中科院分区：
文献类型：
--
作者：
Srivastava, Ankita;Yano, Jason;Okada, Kengo
人GPR 40受体（hGPR 40），也称为游离脂肪酸受体1（FFAR 1），是一种G蛋白偶联受体，可结合长链游离脂肪酸，增强葡萄糖依赖性胰岛素分泌（1）。因此，通过用部分或完全激动剂靶向hGPR 40来治疗2型糖尿病（2）是可能的。TAK-875或法昔利芬是一种口服的、强效的、选择性的hGPR 40受体部分激动剂（3），已进入III期临床试验，用于潜在的2型糖尿病治疗（4）。来自临床研究的数据表明，TAK-875是hGPR 40的变构调节剂（参考文献3），在糖尿病患者中显示出血糖控制改善和低血糖风险降低（5）。在此，我们报告了与TAK-875结合的hGPR 40受体的晶体结构（分辨率为2.3埃）。共复合物结构揭示了TAK-875的独特结合模式，并表明最可能通过脂质双层进入非典型结合口袋。配体结合口袋中广泛电荷网络的原子细节揭示了先前研究中未发现的其他相互作用，有助于清楚了解TAK-875与受体的结合。hGPR 40-TAK-875结构还提供了多种配体与受体的合理结合的见解，这在放射性配体结合（6）和Ca 2+内流试验研究（3）中观察到。跨膜螺旋结构与其他G蛋白偶联受体的比较表明，结晶TAK-875结合的hGPR 40复合物处于非活性样状态。
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(1). Novel treatments for type-2 diabetes mellitus(2) are therefore possible by targeting hGPR40 with partial or full agonists. TAK-875, or fasiglifam, is an orally available, potent and selective partial agonist(3) of hGPR40 receptor, which reached phase III clinical trials for the potential treatment of type-2 diabetes mellitus(4). Data from clinical studies indicate that TAK-875, which is anago-allosteric modulator of hGPR40 (ref. 3), demonstrates improved glycaemic control and low hypoglycaemic risk in diabetic patients(5). Here we report the crystal structure of hGPR40 receptor bound to TAK-875 at 2.3 angstrom 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(6) and Ca2+ influx assay studies(3). 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.