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-Structure paper
| Title | Cryo-EM structure of the dual incretin receptor agonist, peptide-19, in complex with the glucagon-like peptide-1 receptor. |
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| Journal, issue, pages | Biochem Biophys Res Commun, Vol. 578, Page 84-90, Year 2021 |
| Publish date | Nov 12, 2021 |
Authors | Rachel M Johnson / Xin Zhang / Sarah J Piper / Theodore J Nettleton / Teresa H Vandekolk / Christopher J Langmead / Radostin Danev / Patrick M Sexton / Denise Wootten / ![]() |
| PubMed Abstract | 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 ...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 extracellular 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. |
External links | Biochem Biophys Res Commun / PubMed:34547628 |
| Methods | EM (single particle) |
| Resolution | 2.14 Å |
| Structure data | EMDB-24680, PDB-7rtb: |
| Chemicals | ![]() ChemComp-HOH: |
| Source |
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Keywords | MEMBRANE PROTEIN / Glucagon-Like peptide-1 Receptor (GLP-1R) / Peptide-19 cryo-EM |
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