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

The X-ray crystal structure of human GPR40 receptor in the presence of TAK-875, an orally available, potent and selective human GPR40 agonist. The G-protein-coupled receptor (GPCR) human GPR40 (hGPR40, also known as free fatty-acid receptor 1) is an attractive therapeutic target for the treatment of type-2 diabetes mellitus. It is a membrane protein expressed primarily in pancreatic β-cells and intestinal enteroendocrine cells and it acts as a nutrient sensor, enhancing insulin secretion and glucagon-like-peptide 1 secretion. This study reports the atomic details of hGPR40 in complex with TAK-875 (fasiglifam), a partial GPR40 agonist currently in phase III clinical trials. The structure reveals that TAK-875 binds in an usual way, and suggests that that TAK-875 and natural substrates enter the receptor binding pocket through the lipid bilayer. 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 secretion1. Novel treatments for type-2 diabetes mellitus2 are therefore possible by targeting hGPR40 with partial or full agonists. TAK-875, or fasiglifam, is an orally available, potent and selective partial agonist3 of hGPR40 receptor, which reached phase III clinical trials for the potential treatment of type-2 diabetes mellitus4. 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 patients5. Here we report the crystal structure of hGPR40 receptor bound to TAK-875 at 2.3 A 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 binding6 and Ca2+ influx assay studies3. 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.