Cryo-EM structure of the dual incretin receptor agonist, peptide-19, in complex with the glucagon-like peptide-1 receptor

Rachel M. Johnson, Xin Zhang, Sarah J. Piper, Theodore J. Nettleton, Teresa H. Vandekolk, Christopher J. Langmead, Radostin Danev, Patrick M. Sexton, Denise Wootten

Research output: Contribution to journalArticleResearchpeer-review

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 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.

Original languageEnglish
Pages (from-to)84-90
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume578
DOIs
Publication statusPublished - 12 Nov 2021

Keywords

  • Conformational dynamics
  • Cryo-EM
  • Dual agonist
  • GIPR
  • GLP-1R

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