Molecular modeling of the three-dimensional structure of GLP-1R and its interactions with several agonists

J Mol Model. 2009 Jan;15(1):53-65. doi: 10.1007/s00894-008-0372-2. Epub 2008 Oct 22.

Abstract

Glucagon-like peptide-1 receptor (GLP-1R) is a promising molecular target for developing drugs treating type 2 diabetes. We have predicted the complete three-dimensional structure of GLP-1R and the binding modes of several GLP-1R agonists, including GLP-1, Boc5, and Cpd1, through a combination of homology modeling, molecular docking, and long-time molecular dynamics simulation on a lipid bilayer. Our model can reasonably interpret the results of a number of mutation experiments regarding GLP-1R as well as the successful modification to GLP-1 by Liraglutide. Our model is also validated by a recently revealed crystal structure of the extracellular domain of GLP-1R. An activation mechanism of GLP-1R agonists is proposed based on the principal component analysis and normal mode analysis on our predicted GLP-1R structure. Before the complete structure of GLP-1R is determined through experimental means, our model may serve as a valuable reference for characterizing the interactions between GLP-1R and its agonists.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Computer Simulation*
  • Cyclobutanes / chemistry*
  • Cyclobutanes / therapeutic use
  • Diabetes Mellitus, Type 2 / drug therapy
  • Glucagon-Like Peptide-1 Receptor
  • Humans
  • Lipid Bilayers / chemistry*
  • Models, Molecular*
  • Rats
  • Receptors, Glucagon / agonists*

Substances

  • Boc5 compound
  • Cyclobutanes
  • GLP1R protein, human
  • Glp1r protein, rat
  • Glucagon-Like Peptide-1 Receptor
  • Lipid Bilayers
  • Receptors, Glucagon