6b3j | pdb_00006b3j

3.3 angstrom phase-plate cryo-EM structure of a biased agonist-bound human GLP-1 receptor-Gs complex

Loading... Status: waiting for Mol* initialization Structural highlights 6b3j is a 6 chain structure with sequence from Camelus glama and Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Gene: GLP1R (HUMAN), GNAS, GNAS1, GSP (HUMAN), GNB1 (HUMAN), GNG2 (HUMAN) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [GNAS2_HUMAN] Pseudopseudohypoparathyroidism;Pseudohypoparathyroidism type 1A;Progressive osseous heteroplasia;Polyostotic fibrous dysplasia;Monostotic fibrous dysplasia;Pseudohypoparathyroidism type 1C;Pseudohypoparathyroidism type 1B;McCune-Albright syndrome. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. Most affected individuals have defects in methylation of the gene. In some cases microdeletions involving the STX16 appear to cause loss of methylation at exon A/B of GNAS, resulting in PHP1B. Paternal uniparental isodisomy have also been observed. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. Function [GBB1_HUMAN] Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction. [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. [GNAS2_HUMAN] Guanine nucleotide-binding proteins (G proteins) function as transducers in numerous signaling pathways controlled by G protein-coupled receptors (GPCRs) (PubMed:17110384). Signaling involves the activation of adenylyl cyclases, resulting in increased levels of the signaling molecule cAMP (PubMed:26206488, PubMed:8702665). GNAS functions downstream of several GPCRs, including beta-adrenergic receptors (PubMed:21488135). Stimulates the Ras signaling pathway via RAPGEF2 (PubMed:12391161). [GBG2_HUMAN] Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction (By similarity). Publication Abstract from PubMed The class B glucagon-like peptide-1 (GLP-1) G protein-coupled receptor is a major target for the treatment of type 2 diabetes and obesity. Endogenous and mimetic GLP-1 peptides exhibit biased agonism-a difference in functional selectivity-that may provide improved therapeutic outcomes. Here we describe the structure of the human GLP-1 receptor in complex with the G protein-biased peptide exendin-P5 and a Galphas heterotrimer, determined at a global resolution of 3.3 A. At the extracellular surface, the organization of extracellular loop 3 and proximal transmembrane segments differs between our exendin-P5-bound structure and previous GLP-1-bound GLP-1 receptor structure. At the intracellular face, there was a six-degree difference in the angle of the Galphas-alpha5 helix engagement between structures, which was propagated across the G protein heterotrimer. In addition, the structures differed in the rate and extent of conformational reorganization of the Galphas protein. Our structure provides insights into the molecular basis of biased agonism. Phase-plate cryo-EM structure of a biased agonist-bound human GLP-1 receptor-Gs complex.,Liang YL, Khoshouei M, Glukhova A, Furness SGB, Zhao P, Clydesdale L, Koole C, Truong TT, Thal DM, Lei S, Radjainia M, Danev R, Baumeister W, Wang MW, Miller LJ, Christopoulos A, Sexton PM, Wootten D Nature. 2018 Mar 1;555(7694):121-125. doi: 10.1038/nature25773. Epub 2018 Feb 21. PMID:29466332 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Annexin 3D structures Transducin 3D structures

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