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
  • 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. [email protected].
  • 12. School of Biological Sciences, University of Essex, Colchester, CO4 3SQ, UK. [email protected].
  • 13. Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia. [email protected].
  • 14. ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia. [email protected].
  • 15. Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia. [email protected].
  • 16. ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia. [email protected].
  • 17. Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia. [email protected].
  • 18. ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia. [email protected].
  • # 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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