Journal
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Volume 578, Issue -, Pages 84-90Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2021.09.016
Keywords
GLP-1R; Dual agonist; Cryo-EM; GIPR; Conformational dynamics
Categories
Funding
- National Health and Medical Research Council of Australia [1150083, 1126857, 1184726, 1154434, 1155302]
- Australian Research Council [IC200100052]
- Takeda Science Foundation
- Japan Science and Technology Agency PRESTO [18069571]
- National Health and Medical Research Council of Australia [1155302, 1154434, 1126857, 1184726] Funding Source: NHMRC
- Australian Research Council [IC200100052] Funding Source: Australian Research Council
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Dual agonists that can activate both GLP-1R and GIPR have high efficacy in treating metabolic disease, with peptide-19 being a potent prototype. The complex of peptide-19:GLP-1R:Gs exhibits a more open binding pocket and high dynamicity in the TM binding pocket. This structure provides unique insights into GLP-1R activation by this dual agonist.
Dual agonists that can activate both the glucagon-like peptide-1 receptor (GLP-1R) and the gastric inhibitory polypeptide receptor (GIPR) have demonstrated high efficacy for the treatment of metabolic disease. Peptide-19 is a prototypical dual agonist that has high potency at both GLP-1R and GIPR but has a distinct signalling profile relative to the native peptides at the cognate receptors. In this study, we solved the structure of peptide-19 bound to the GLP-1R in complex with Gs protein, and compared the structure and dynamics of this complex to that of published structures of GLP-1R:Gs in complex with other receptor agonists. Unlike other peptide-bound receptor complexes, peptide-19:GLP-1R:Gs demonstrated a more open binding pocket where transmembrane domain (TM) 6, TM7 and the interconnecting extra cellular loop 3 (ECL3) were located away from the peptide, with no interactions between peptide-19 and TM6/ECL3. Analysis of conformational variance of the complex revealed that peptide-19 was highly dynamic and underwent binding and unbinding motions facilitated by the more open TM binding pocket. Both the consensus structure of the GLP-1R complex with peptide-19 and the dynamics of this complex were distinct from previously described GLP-1R structures providing unique insights into the mode of GLP-1R activation by this dual agonist. (c) 2021 Elsevier Inc. All rights reserved.
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