title: High-resolution structure of the human GPR40 receptor bound to allosteric agonist TAK-875.
abstract: 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 selective 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 Ca(2+) 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.
authors.affiliation: 1] Department of Structural Biology and Core Sciences &Technology, Takeda California, 10410 Science Center Drive, San Diego, California 92121, USA [2].
authors.forename: Ankita
authors.initials: A
authors.lastname: Srivastava
authors.affiliation: 1] Department of Structural Biology and Core Sciences &Technology, Takeda California, 10410 Science Center Drive, San Diego, California 92121, USA [2].
authors.forename: Jason
authors.initials: J
authors.lastname: Yano
authors.affiliation: Biomolecular Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Hirozane
authors.affiliation: Department of Structural Biology and Core Sciences &Technology, Takeda California, 10410 Science Center Drive, San Diego, California 92121, USA.
authors.forename: Georgia
authors.initials: G
authors.lastname: Kefala
authors.affiliation: 1] Department of Structural Biology and Core Sciences &Technology, Takeda California, 10410 Science Center Drive, San Diego, California 92121, USA [2] Beryllium, Membrane Protein Sciences, 7869 NE Day Road West, Bainbridge Island, Washington 98110, USA (F.G.); Dart Neuroscience, 12278 Scripps Summit Drive, San Diego, California 92131, USA (K.A. and J.N.).
authors.forename: Franz
authors.initials: F
authors.lastname: Gruswitz
authors.affiliation: Department of Structural Biology and Core Sciences &Technology, Takeda California, 10410 Science Center Drive, San Diego, California 92121, USA.
authors.forename: Gyorgy
authors.initials: G
authors.lastname: Snell
authors.affiliation: Department of Structural Biology and Core Sciences &Technology, Takeda California, 10410 Science Center Drive, San Diego, California 92121, USA.
authors.forename: Weston
authors.initials: W
authors.lastname: Lane
authors.affiliation: Department of Structural Biology and Core Sciences &Technology, Takeda California, 10410 Science Center Drive, San Diego, California 92121, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Ivetac
authors.affiliation: 1] Department of Structural Biology and Core Sciences &Technology, Takeda California, 10410 Science Center Drive, San Diego, California 92121, USA [2] Beryllium, Membrane Protein Sciences, 7869 NE Day Road West, Bainbridge Island, Washington 98110, USA (F.G.); Dart Neuroscience, 12278 Scripps Summit Drive, San Diego, California 92131, USA (K.A. and J.N.).
authors.forename: Kathleen
authors.initials: K
authors.lastname: Aertgeerts
authors.affiliation: 1] Department of Structural Biology and Core Sciences &Technology, Takeda California, 10410 Science Center Drive, San Diego, California 92121, USA [2] Beryllium, Membrane Protein Sciences, 7869 NE Day Road West, Bainbridge Island, Washington 98110, USA (F.G.); Dart Neuroscience, 12278 Scripps Summit Drive, San Diego, California 92131, USA (K.A. and J.N.).
authors.forename: Jasmine
authors.initials: J
authors.lastname: Nguyen
authors.affiliation: Department of Structural Biology and Core Sciences &Technology, Takeda California, 10410 Science Center Drive, San Diego, California 92121, USA.
authors.forename: Andy
authors.initials: A
authors.lastname: Jennings
authors.affiliation: Biomolecular Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Okada
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D001572:Benzofurans / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D054333:Drug Partial Agonism; D006801:Humans; D008024:Ligands; D008051:Lipid Bilayers / Q000378:metabolism; D008958:Models, Molecular; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000737:chemistry* / Q000378:metabolism; D040681:Structural Homology, Protein; D013450:Sulfones / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D013499:Surface Properties
chemical_list: D001572:Benzofurans; C473034:FFAR1 protein, human; D008024:Ligands; D008051:Lipid Bilayers; D043562:Receptors, G-Protein-Coupled; D013450:Sulfones; C557331:TAK-875