6B3J

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

6B3J の概要

• エントリーDOI: 10.2210/pdb6b3j/pdb
• EMDBエントリー: 7039
• 分子名称: Glucagon-like peptide 1 receptor, Exendin-P5, Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, ... (6 entities in total)
• 機能のキーワード: 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
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 168196.47

構造登録者

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. (登録日: 2017-09-22, 公開日: 2018-02-21, 最終更新日: 2024-10-23)

主引用文献

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

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: 29466332
DOI: 10.1038/nature25773

実験手法

ELECTRON MICROSCOPY (3.3 Å)