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 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 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.
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Protein Data Bank
Coordinates and structure factors have been deposited in Protein Data Bank under accession number 4PHU.
We thank K. P. Wilson, M. Hixon and K. Goodwill for review and feedback on the manuscript; T. Ho and S. Okubo for molecular cloning support; T. Sjoberg for membrane preparation; and C. Dillard for cell culture support. We also thank the staff of the Berkeley Center for Structural Biology, Lawrence Berkeley National Laboratory, which operates Advanced Light Source beamline 5.0.3, and the staff of GM/CA, Argonne National Laboratory, which operates Advanced Photon Source beamline 23ID-D. The Berkeley Center for Structural Biology is supported in part by the National Institutes of Health and National Institute of General Medical Sciences. The GM/CA has been funded in whole or in part with Federal funds from the National Cancer Institute (Y1-CO-1020) and the National Institute of General Medical Sciences (Y1-GM-1104). The Advanced Light Source and Advanced Photon Source are supported by the Director, Office of Science, Office of Basic Energy Sciences of the US Department of Energy under contract numbers DE-AC02-05CH11231 and DE-AC02-06CH11357, respectively.