National Health and Medical Research Council (NHMRC, Australia)
1061044
Australia
National Health and Medical Research Council (NHMRC, Australia)
1126857
Australia
National Health and Medical Research Council (NHMRC, Australia)
1065410
Australia
National Health and Medical Research Council (NHMRC, Australia)
1055134
Australia
Citation
Journal: Nature / Year: 2018 Title: Phase-plate cryo-EM structure of a biased agonist-bound human GLP-1 receptor-Gs complex. Authors: Yi-Lynn Liang / Maryam Khoshouei / Alisa Glukhova / Sebastian G B Furness / Peishen Zhao / Lachlan Clydesdale / Cassandra Koole / Tin T Truong / David M Thal / Saifei Lei / Mazdak Radjainia ...Authors: Yi-Lynn Liang / Maryam Khoshouei / Alisa Glukhova / Sebastian G B Furness / Peishen Zhao / Lachlan Clydesdale / Cassandra Koole / Tin T Truong / David M Thal / Saifei Lei / Mazdak Radjainia / Radostin Danev / Wolfgang Baumeister / Ming-Wei Wang / Laurence J Miller / Arthur Christopoulos / Patrick M Sexton / Denise Wootten / 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- ...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.
History
Header (metadata) release
Mar 29, 2017
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Deposition
Sep 22, 2017
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Map release
Feb 21, 2018
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Update
Aug 12, 2020
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Current status
Aug 12, 2020
Processing site: RCSB / Status: Released
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Structure visualization
Movie
Surface view with section colored by density value
Entire : Complex of a full-length, active-state glucagon-like peptide-1 re...
Entire
Name: Complex of a full-length, active-state glucagon-like peptide-1 receptor with exendin-P5 ligand, heterotrimeric Gs protein and nanobody 35.
Components
Complex: Complex of a full-length, active-state glucagon-like peptide-1 receptor with exendin-P5 ligand, heterotrimeric Gs protein and nanobody 35.
Protein or peptide: Glucagon-like peptide 1 receptor
Protein or peptide: Exendin-P5
Protein or peptide: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
Protein or peptide: Nanobody 35
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Supramolecule #1: Complex of a full-length, active-state glucagon-like peptide-1 re...
Supramolecule
Name: Complex of a full-length, active-state glucagon-like peptide-1 receptor with exendin-P5 ligand, heterotrimeric Gs protein and nanobody 35. type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
3C5T was rigid body fitted with minimal manual adjustments. The rest of the chain R and chains A,B,G,N were extensively remodeled. Chain P was built de novo.
Output model
PDB-6b3j: 3.3 angstrom phase-plate cryo-EM structure of a biased agonist-bound human GLP-1 receptor-Gs complex
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