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

Graham M West1, Francis S Willard2, Kyle W Sloop3

  • 1Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, Florida, United States of America; Mass Spectrometry and Proteomics, The Scripps Research Institute, Scripps Florida, Jupiter, Florida, United States of America.

Plos One
|September 3, 2014
PubMed

Insights

Hydrogen/deuterium exchange (HDX) reveals how peptide ligands interact with the glucagon-like peptide-1 receptor (GLP-1R) extracellular domain. This method validates binding for small molecule ligands, aiding type 2 diabetes mellitus (T2DM) drug development.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Structural Biology

Background:

  • The glucagon-like peptide-1 receptor (GLP-1R) is a key therapeutic target for type 2 diabetes mellitus (T2DM).
  • GLP-1R, a class B G protein-coupled receptor (GPCR), has an N-terminal extracellular ligand-binding domain.
  • Modified peptide agonists can act as antagonists by binding without full receptor activation.

Purpose of the Study:

  • To investigate alterations in hydrogen bonding networks of GLP-1R peptide ligands and its N-terminal extracellular domain (nGLP-1R) upon ligand binding using Hydrogen/deuterium exchange (HDX).
  • To establish HDX as a platform for validating direct binding of small molecule ligands to nGLP-1R.

Main Methods:

  • Hydrogen/deuterium exchange (HDX) mass spectrometry.
  • Analysis of peptide ligand (exendin-4 and exendin-4[9-39]) and nGLP-1R interactions.
  • Assessment of ligand stability in the presence of nonionic detergents.

Main Results:

  • HDX detected differential stabilization of hydrogen bonding networks for agonist exendin-4 versus antagonist exendin-4[9-39].
  • Ligand binding stabilized hydrogen bonding networks in the N-terminal helix of both exendin-4 and exendin-4[9-39].
  • HDX confirmed ligand-induced stabilization within the nGLP-1R structure and validated direct binding of small molecule ligands.

Conclusions:

  • HDX is effective in characterizing ligand-receptor interactions at the molecular level for GLP-1R.
  • The study validates HDX as a method for confirming direct binding of small molecule ligands to the GLP-1R extracellular domain.
  • Findings contribute to understanding GLP-1R pharmacology and developing novel T2DM therapeutics.

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