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

Liang, Y.-L., Khoshouei, M., Glukhova, A., Furness, S. G. B., Zhao, P., Clydesdale, L., et al. (2018). Phase-plate cryo-EM structure of a biased agonist-bound human GLP-1 receptor-Gs complex. Nature, 555(7694), 121-125. doi:10.1038/nature25773.

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 Creators:
Liang, Yi-Lynn1, Author
Khoshouei, Maryam2, Author              
Glukhova, Alisa1, Author
Furness, Sebastian G. B.1, Author
Zhao, Peishen1, Author
Clydesdale, Lachlan1, Author
Koole, Cassandra1, Author
Truong, Tin T.1, Author
Thal, David M.1, Author
Lei, Saifei1, Author
Radjainia, Mazdak1, Author
Danev, Radostin2, Author              
Baumeister, Wolfgang2, Author              
Wang, Ming-Wei1, Author
Miller, Laurence J.1, Author
Christopoulos, Arthur1, Author
Sexton, Patrick M.1, Author
Wootten, Denise1, Author
Affiliations:
1external, ou_persistent22              
2Baumeister, Wolfgang / Molecular Structural Biology, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565142              

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Free keywords: GLUCAGON-LIKE PEPTIDE-1; PROTEIN-COUPLED RECEPTOR; ELECTRON-MICROSCOPY; CRYSTAL-STRUCTURE; LIGAND-BINDING; ACTIVATION; DOMAIN; RESIDUES; MUTANT; MODULATIONScience & Technology - Other Topics;
 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(1). Endogenous and mimetic GLP-1 peptides exhibit biased agonism-a difference in functional selectivity-that may provide improved therapeutic outcomes1. Here we describe the structure of the human GLP-1 receptor in complex with the G protein-biased peptide exendin-P5 and a G alpha(s) heterotrimer, determined at a global resolution of 3.3 angstrom. 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(2). At the intracellular face, there was a six-degree difference in the angle of the G alpha(s)-alpha 5 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 G alpha(s) protein. Our structure provides insights into the molecular basis of biased agonism.

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Language(s): eng - English
 Dates: 2018-02-212018-03
 Publication Status: Published in print
 Pages: 20
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: ISI: 000426247600044
DOI: 10.1038/nature25773
 Degree: -

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Title: Nature
  Abbreviation : Nature
Source Genre: Journal
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Publ. Info: London : Nature Publishing Group
Pages: - Volume / Issue: 555 (7694) Sequence Number: - Start / End Page: 121 - 125 Identifier: ISSN: 0028-0836
CoNE: https://pure.mpg.de/cone/journals/resource/954925427238