2. Academic Validation
  3. Dynamics of GLP-1R peptide agonist engagement are correlated with kinetics of G protein activation

Dynamics of GLP-1R peptide agonist engagement are correlated with kinetics of G protein activation

  • Nat Commun. 2022 Jan 10;13(1):92. doi: 10.1038/s41467-021-27760-0.
Giuseppe Deganutti # 1 2,  Yi-Lynn Liang # 3 4,  Xin Zhang # 3 5,  Maryam Khoshouei # 6 7,  Lachlan Clydesdale # 3,  Matthew J Belousoff 3 5,  Hari Venugopal 8,  Tin T Truong 3,  Alisa Glukhova 3 9,  Andrew N Keller 3,  Karen J Gregory 3,  Katie Leach 3,  Arthur Christopoulos 3 5,  Radostin Danev 10,  Christopher A Reynolds 11 12,  Peishen Zhao 13 14,  Patrick M Sexton 15 16,  Denise Wootten 17 18
Affiliations

Affiliations

  • 1 Centre for Sport, Exercise and Life Sciences, Coventry University, CV1 5FB, Coventry, UK.
  • 2 School of Biological Sciences, University of Essex, Colchester, CO4 3SQ, UK.
  • 3 Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia.
  • 4 Confo Therapeutics, Technologiepark 94, Ghent (Zwijnaarde), 9052, Belgium.
  • 5 ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia.
  • 6 Department of Molecular Structural Biology, Max Planck Institute of Biochemistry, 82152, Martinsried, Germany.
  • 7 Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, Switzerland.
  • 8 Ramaciotti Centre for Cryo-Electron Microscopy, Monash University, Clayton, VIC, 3168, Australia.
  • 9 Walter and Eliza Hall Institute, Parkville, VIC, 3052, Australia.
  • 10 Graduate School of Medicine, University of Tokyo, N415, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
  • 11 Centre for Sport, Exercise and Life Sciences, Coventry University, CV1 5FB, Coventry, UK. ad5291@coventry.ac.uk.
  • 12 School of Biological Sciences, University of Essex, Colchester, CO4 3SQ, UK. ad5291@coventry.ac.uk.
  • 13 Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia. elva.zhao@monash.edu.
  • 14 ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia. elva.zhao@monash.edu.
  • 15 Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia. patrick.sexton@monash.edu.
  • 16 ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia. patrick.sexton@monash.edu.
  • 17 Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia. denise.wootten@monash.edu.
  • 18 ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia. denise.wootten@monash.edu.
  • # Contributed equally.
PMID: 35013280 DOI: 10.1038/s41467-021-27760-0
Abstract

The glucagon-like peptide-1 receptor (GLP-1R) has broad physiological roles and is a validated target for treatment of metabolic disorders. Despite recent advances in GLP-1R structure elucidation, detailed mechanistic understanding of how different Peptides generate profound differences in G protein-mediated signalling is still lacking. Here we combine cryo-electron microscopy, molecular dynamics simulations, receptor mutagenesis and pharmacological assays, to interrogate the mechanism and consequences of GLP-1R binding to four peptide agonists; glucagon-like peptide-1, oxyntomodulin, exendin-4 and exendin-P5. These data reveal that distinctions in peptide N-terminal interactions and dynamics with the GLP-1R transmembrane domain are reciprocally associated with differences in the allosteric coupling to G proteins. In particular, transient interactions with residues at the base of the binding cavity correlate with enhanced kinetics for G protein activation, providing a rationale for differences in G protein-mediated signalling efficacy from distinct agonists.

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