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Phase-plate cryo-EM Structure of a Biased Agonist-Bound Human GLP-1 receptor-Gs Complex

Phase-plate cryo-EM Structure of a Biased Agonist-Bound Human GLP-1 receptor-Gs Complex

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, etc.

Nature. 2018 Mar 1;555(7694):121-125.

PMID: 29466332

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 Gαs 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 Gαs protein. Our structure provides insights into the molecular basis of biased agonism.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP281209710	Glucagon-Like Peptide 1 Receptor Agonist - CAS 281209-71-0		281209-71-0	Price

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