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

Original Paper

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.

Figure

Comparison of our predicted model of rGLP-1R (left) with the recently revealed crystal structure of hGLP-1R (right)

Keywords

GLP-1R GLP-1R agonist Homology modeling Molecular docking Molecular dynamics 

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Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  1. 1.State Key Laboratory of Bioorganic Chemistry, Shanghai Institute of Organic ChemistryChinese Academy of SciencesShanghaiPeople’s Republic of China

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