6vcb | pdb_00006vcb

Cryo-EM structure of the Glucagon-like peptide-1 receptor in complex with G protein, GLP-1 peptide and a positive allosteric modulator

spinqualitylabelsall models 6vcb, resolution 3.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6vcb is a 6 chain structure with sequence from Homo sapiens and Lama glama. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.3Å Ligands: QW7 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function GLP1R_HUMAN This is a receptor for glucagon-like peptide 1. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase. Publication Abstract from PubMed Drugs that promote the association of protein complexes are an emerging therapeutic strategy. We report discovery of a G protein-coupled receptor (GPCR) ligand that stabilizes an active state conformation by cooperatively binding both the receptor and orthosteric ligand, thereby acting as a 'molecular glue'. LSN3160440 is a positive allosteric modulator of the GLP-1R optimized to increase the affinity and efficacy of GLP-1(9-36), a proteolytic product of GLP-1(7-36). The compound enhances insulin secretion in a glucose-, ligand- and GLP-1R-dependent manner. Cryo-electron microscopy determined the structure of the GLP-1R bound to LSN3160440 in complex with GLP-1 and heterotrimeric Gs. The modulator binds high in the helical bundle at an interface between TM1 and TM2, allowing access to the peptide ligand. Pharmacological characterization showed strong probe dependence of LSN3160440 for GLP-1(9-36) versus oxyntomodulin that is driven by a single residue. Our findings expand protein-protein modulation drug discovery to uncompetitive, active state stabilizers for peptide hormone receptors. Structural insights into probe-dependent positive allosterism of the GLP-1 receptor.,Bueno AB, Sun B, Willard FS, Feng D, Ho JD, Wainscott DB, Showalter AD, Vieth M, Chen Q, Stutsman C, Chau B, Ficorilli J, Agejas FJ, Cumming GR, Jimenez A, Rojo I, Kobilka TS, Kobilka BK, Sloop KW Nat Chem Biol. 2020 Oct;16(10):1105-1110. doi: 10.1038/s41589-020-0589-7. Epub, 2020 Jul 20. PMID:32690941 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Glucagon-like peptide receptor 3D structures Transducin 3D structures

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