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

25 Citations (Scopus)

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
  • ARC Industrial Transformation Training Centre for Cryo-Electron Microscopy of Membrane Proteins for Drug Discovery

    Sexton, P. (Primary Chief Investigator (PCI)), Rouiller, I. (Chief Investigator (CI)), Wootten, D. (Chief Investigator (CI)), van Oijen, A. (Chief Investigator (CI)), Parker, M. W. (Chief Investigator (CI)), Lucet, I. (Partner Investigator (PI)), Griffin, M. D. W. (Chief Investigator (CI)), Adams, D. J. (Chief Investigator (CI)), Czabotar, P. E. (Partner Investigator (PI)), Flocco, M. (Partner Investigator (PI)), Han, S. (Partner Investigator (PI)), Shepherd, R. (Partner Investigator (PI)), Ciferri, C. (Partner Investigator (PI)), Williams, P. A. (Partner Investigator (PI)), Brown, D. (Partner Investigator (PI)), Schreuder, H. (Partner Investigator (PI)), Reedtz-Runge, S. (Partner Investigator (PI)), Drinkwater, C. (Partner Investigator (PI)), Howard, B. L. (Partner Investigator (PI)), Betigeri, G. (Partner Investigator (PI)), Pryor, E. (Partner Investigator (PI)), How, J. (Project Manager) & Christopoulos, T. (Chief Investigator (CI))

    Boehringer Ingelheim (Germany), AstraZeneca (United Kingdom)

    23/03/2123/03/27

    Project: Research

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