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Glucagon-like peptide-1 receptor ligand interactions: structural cross talk between ligands and the extracellular domain

Academic Article
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Overview

authors

  • West, Graham
  • Willard, F. S.
  • Sloop, K. W.
  • Showalter, A. D.
  • Pascal, B. D.
  • Griffin, Patrick

publication date

  • September 2014

journal

  • PLoS One  Journal

abstract

  • Activation of the glucagon-like peptide-1 receptor (GLP-1R) in pancreatic β-cells potentiates insulin production and is a current therapeutic target for the treatment of type 2 diabetes mellitus (T2DM). Like other class B G protein-coupled receptors (GPCRs), the GLP-1R contains an N-terminal extracellular ligand binding domain. N-terminal truncations on the peptide agonist generate antagonists capable of binding to the extracellular domain, but not capable of activating full length receptor. The main objective of this study was to use Hydrogen/deuterium exchange (HDX) to identify how the amide hydrogen bonding network of peptide ligands and the extracellular domain of GLP-1R (nGLP-1R) were altered by binding interactions and to then use this platform to validate direct binding events for putative GLP-1R small molecule ligands. The HDX studies presented here for two glucagon-like peptide-1 receptor (GLP-1R) peptide ligands indicates that the antagonist exendin-4[9-39] is significantly destabilized in the presence of nonionic detergents as compared to the agonist exendin-4. Furthermore, HDX can detect stabilization of exendin-4 and exendin-4[9-39] hydrogen bonding networks at the N-terminal helix [Val19 to Lys27] upon binding to the N-terminal extracellular domain of GLP-1R (nGLP-1R). In addition we show hydrogen bonding network stabilization on nGLP-1R in response to ligand binding, and validate direct binding events with the extracellular domain of the receptor for putative GLP-1R small molecule ligands.

subject areas

  • Amino Acid Sequence
  • Crystallography, X-Ray
  • Deuterium Exchange Measurement
  • Glucagon-Like Peptide-1 Receptor
  • Ligands
  • Molecular Sequence Data
  • Peptides
  • Protein Structure, Tertiary
  • Receptors, Glucagon
  • Small Molecule Libraries
  • Venoms
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Identity

PubMed Central ID

  • PMC4152014

International Standard Serial Number (ISSN)

  • 1932-6203

Digital Object Identifier (DOI)

  • 10.1371/journal.pone.0105683

PubMed ID

  • 25180755
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Additional Document Info

start page

  • e105683

volume

  • 9

issue

  • 9

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