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

doi:10.1016/j.bbrc.2021.09.016

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

Biochem Biophys Res Commun. 2021 Nov 12:578:84-90. doi: 10.1016/j.bbrc.2021.09.016. Epub 2021 Sep 16.

Authors

Rachel M Johnson¹, Xin Zhang¹, Sarah J Piper¹, Theodore J Nettleton², Teresa H Vandekolk², Christopher J Langmead¹, Radostin Danev³, Patrick M Sexton⁴, Denise Wootten⁵

Affiliations

¹ Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, 3052, Victoria, Australia; ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, 3052, Victoria, Australia.
² Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, 3052, Victoria, Australia.
³ Graduate School of Medicine, University of Tokyo, N415, 7-3-1 Hongo, Bunkyo-ku, 113-0033, Tokyo, Japan.
⁴ Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, 3052, Victoria, Australia; ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, 3052, Victoria, Australia. Electronic address: Patrick.sexton@monash.edu.
⁵ Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, 3052, Victoria, Australia; ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, 3052, Victoria, Australia. Electronic address: denise.wootten@monash.edu.

PMID: 34547628
DOI: 10.1016/j.bbrc.2021.09.016

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.

Keywords: Conformational dynamics; Cryo-EM; Dual agonist; GIPR; GLP-1R.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cryoelectron Microscopy / methods
Glucagon-Like Peptide-1 Receptor / agonists
Glucagon-Like Peptide-1 Receptor / chemistry*
Glucagon-Like Peptide-1 Receptor / metabolism*
Peptides / chemistry*
Peptides / metabolism*
Protein Domains
Protein Structural Elements

Substances

Glucagon-Like Peptide-1 Receptor
Peptides