5tzr | pdb_00005tzr

GPR40 in complex with partial agonist MK-8666

spinqualitylabelsall models 5tzr, resolution 2.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5tzr is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 1PE, MK6, MLI, NA, OLC Related: 5tzy Activity: Lysozyme, with EC number 3.2.1.17 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [FFAR1_HUMAN] Receptor for medium and long chain saturated and unsaturated fatty acids. Binding of the ligand increase intracellular calcium concentration and amplify glucose-stimulated insulin secretion. The activity of this receptor is mediated by G-proteins that activate phospholipase C. Seems to act through a G(q) and G(i)-mediated pathway. Publication Abstract from PubMed Clinical studies indicate that partial agonists of the G-protein-coupled, free fatty acid receptor 1 GPR40 enhance glucose-dependent insulin secretion and represent a potential mechanism for the treatment of type 2 diabetes mellitus. Full allosteric agonists (AgoPAMs) of GPR40 bind to a site distinct from partial agonists and can provide additional efficacy. We report the 3.2-A crystal structure of human GPR40 (hGPR40) in complex with both the partial agonist MK-8666 and an AgoPAM, which exposes a novel lipid-facing AgoPAM-binding pocket outside the transmembrane helical bundle. Comparison with an additional 2.2-A structure of the hGPR40-MK-8666 binary complex reveals an induced-fit conformational coupling between the partial agonist and AgoPAM binding sites, involving rearrangements of the transmembrane helices 4 and 5 (TM4 and TM5) and transition of the intracellular loop 2 (ICL2) into a short helix. These conformational changes likely prime GPR40 to a more active-like state and explain the binding cooperativity between these ligands. Structural basis for the cooperative allosteric activation of the free fatty acid receptor GPR40.,Lu J, Byrne N, Wang J, Bricogne G, Brown FK, Chobanian HR, Colletti SL, Di Salvo J, Thomas-Fowlkes B, Guo Y, Hall DL, Hadix J, Hastings NB, Hermes JD, Ho T, Howard AD, Josien H, Kornienko M, Lumb KJ, Miller MW, Patel SB, Pio B, Plummer CW, Sherborne BS, Sheth P, Souza S, Tummala S, Vonrhein C, Webb M, Allen SJ, Johnston JM, Weinglass AB, Sharma S, Soisson SM Nat Struct Mol Biol. 2017 Jul;24(7):570-577. doi: 10.1038/nsmb.3417. Epub 2017, Jun 5. PMID:28581512 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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