Projects per year
Abstract
The glucagon-like peptide-1 receptor (GLP-1R) regulates insulin secretion, carbohydrate metabolism, and appetite and is an important target for treatment of type 2 diabetes and obesity. Multiple GLP-1R agonists have entered into clinical trials, with some, such as semaglutide, progressing to approval. Others, including taspoglutide, failed due to the high incidence of side effects or insufficient efficacy. GLP-1R agonists have a broad spectrum of signaling profiles, but molecular understanding is limited by a lack of structural information on how different agonists engage with the GLP-1R. Here, we report cryoelectron microscopy (cryo-EM) structures and cryo-EM 3D variability analysis of semaglutide- and taspoglutide-bound GLP-1R-Gs protein complexes. These reveal similar peptide interactions to GLP-1 but different motions within the receptor and bound peptides, providing insights into the molecular determinants of GLP-1R peptide engagement.
Original language | English |
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Article number | 109374 |
Number of pages | 15 |
Journal | Cell Reports |
Volume | 36 |
Issue number | 2 |
DOIs | |
Publication status | Published - 13 Jul 2021 |
Keywords
- cryoelectron microscopy
- GLP-1R
- glucagon-like peptide-1 receptor
- GPCR dynamics
- GPCRs
- semaglutide
- tasopglutide
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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.
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
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Translating membrane proteins into therapeutics; from bedside to bench
Sexton, P., Christopoulos, A., Pantelis, C. & Parton, R. G.
1/01/19 → 31/12/23
Project: Research
Equipment
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MASSIVE
Slava Kitaeff (Manager) & David Powell (Manager)
Office of the Vice-Provost (Research and Research Infrastructure)Facility/equipment: Facility