Poster Presentation The 43rd Lorne Conference on Protein Structure and Function 2018

3.3Å phase-plate cryo-EM structure of a biased agonist-bound human GLP-1 receptor-Gs complex (#175)

Yi-Lynn Liang* 1 , Maryam Khoshouei* 2 , Alisa Glukhova* 1 , Sebastian GB Furness 1 , Peishen Zhao 1 , Lachlan Clydesdale 1 , Cassandra Koole 1 , Tin T Truong 1 , David M Thal 1 , Saifei Lei 3 , Mazdak Radjainia 1 4 , Radostin Danev 2 , Wolfgang Baumeister 2 , Ming-Wei Wang 3 5 , Laurence J Miller 1 6 , Arthur Christopoulos 1 , Patrick M Sexton# 1 , Denise Wootten# 1
  1. Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia
  2. Department of Molecular Structural Biology, Max Planck Institute of Biochemistry, Martinsried, Germany
  3. The National Center for Drug Screening and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
  4. FEI, Eindhoven, Netherlands
  5. School of Pharmacy, Fudan University, Shanghai, China
  6. Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Scottsdale, Arizona, USA

The class B glucagon-like peptide-1 (GLP-1) G protein-coupled receptor is a major therapeutic target for treatment of type 2 diabetes and obesity. Endogenous and mimetic GLP-1 peptides exhibit biased agonism that may provide therapeutic differentiation. Here we report the structure of human GLP-1 receptor in complex with the G protein-biased peptide, exendin-P5, and Gαs heterotrimer determined at 3.3 Å global resolution. At the extracellular face of the receptor, there was a distinct organisation of extracellular loop 3 and proximal transmembrane segments, which differ between the exendin-P5 structure and the published GLP-1 bound GLP-1 receptor. At the intracellular face, there was a 6-degree difference in the angle of the Gas-a5 helix engagement between the receptors that was propagated across the G protein heterotrimer, and differences in the rate and extent of conformational reorganisation of the Gαs protein. This new structure provides novel insights into the structural basis of biased agonism.