6B3J
3.3 angstrom phase-plate cryo-EM structure of a biased agonist-bound human GLP-1 receptor-Gs complex
Summary for 6B3J
Entry DOI | 10.2210/pdb6b3j/pdb |
EMDB information | 7039 |
Descriptor | Glucagon-like peptide 1 receptor, Exendin-P5, Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, ... (6 entities in total) |
Functional Keywords | class b g protein-coupled receptor, agonist-receptor-g protein ternary complex, glucagon-like peptide 1 receptor, active-state g protein-coupled receptor, signaling protein, phase plate, phase contrast, single particle cryo-em |
Biological source | Homo sapiens (Human) More |
Total number of polymer chains | 6 |
Total formula weight | 168196.47 |
Authors | Liang, Y.L.,Khoshouei, M.,Glukhova, A.,Furness, S.G.B.,Koole, C.,Zhao, P.,Clydesdale, L.,Thal, D.M.,Radjainia, M.,Danev, R.,Baumeister, W.,Wang, M.W.,Miller, L.J.,Christopoulos, A.,Sexton, P.M.,Wootten, D. (deposition date: 2017-09-22, release date: 2018-02-21, Last modification date: 2024-10-23) |
Primary citation | Liang, Y.L.,Khoshouei, M.,Glukhova, A.,Furness, S.G.B.,Zhao, P.,Clydesdale, L.,Koole, C.,Truong, T.T.,Thal, D.M.,Lei, S.,Radjainia, M.,Danev, R.,Baumeister, W.,Wang, M.W.,Miller, L.J.,Christopoulos, A.,Sexton, P.M.,Wootten, D. Phase-plate cryo-EM structure of a biased agonist-bound human GLP-1 receptor-Gs complex. Nature, 555:121-125, 2018 Cited by PubMed Abstract: 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 Gα heterotrimer, determined at a global resolution of 3.3 Å. 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 Gαs-α5 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 Gα protein. Our structure provides insights into the molecular basis of biased agonism. PubMed: 29466332DOI: 10.1038/nature25773 PDB entries with the same primary citation |
Experimental method | ELECTRON MICROSCOPY (3.3 Å) |
Structure validation
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