Projects per year
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.
Original language | English |
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Article number | 92 |
Number of pages | 18 |
Journal | Nature Communications |
Volume | 13 |
DOIs | |
Publication status | Published - 2022 |
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ARC Industrial Transformation Training Centre for Cryo-Electron Microscopy of Membrane Proteins for Drug Discovery
Sexton, P., Rouiller, I., Wootten, D., van Oijen, A., Parker, M. W., Lucet, I., Griffin, M. D. W., Adams, D. J., Czabotar, P. E., Flocco, M., Han, S., Shepherd, R., Ciferri, C., Williams, P. A., Brown, D., Schreuder, H., Reedtz-Runge, S., Drinkwater, C., Howard, B. L., Betigeri, G., Pryor, E. & How, J.
Boehringer Ingelheim (Germany), AstraZeneca (United Kingdom)
23/03/21 → 22/03/26
Project: Research
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Molecular control of efficacy at glucagon family of receptors
Wootten, D. & Wu, B.
National Health and Medical Research Council (NHMRC) (Australia)
1/01/20 → 31/12/24
Project: Research
Equipment
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Centre for Electron Microscopy (MCEM)
Flame Sorrell (Manager) & Peter Miller (Manager)
Office of the Vice-Provost (Research and Research Infrastructure)Facility/equipment: Facility
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MASSIVE
Slava Kitaeff (Manager) & David Powell (Manager)
Office of the Vice-Provost (Research and Research Infrastructure)Facility/equipment: Facility
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Ramaciotti Centre for Cryo-Electron Microscopy
Georg Ramm (Manager), Simon Andrew Crawford (Operator), Hariprasad Venugopal (Operator), Joan Marea Clark (Operator) & Gediminas Gervinskas (Operator)
Faculty of Medicine Nursing and Health Sciences Research PlatformsFacility/equipment: Facility