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

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.

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

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Acknowledgment

The authors are grateful to the financial supports from the Chinese National Natural Science Foundation (grants 20502031 & 20772149), the Chinese Ministry of Science and Technology (grant 2006AA02Z337), and the Science and Technology Commission of Shanghai Municipality (grants 06PJ14115 & 074319113).

Supporting information available

Three-dimensional structures of the GLP-1R models described in this manuscript are available from the authors upon request.

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Correspondence to Renxiao Wang.

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Lin, F., Wang, R. Molecular modeling of the three-dimensional structure of GLP-1R and its interactions with several agonists. J Mol Model 15, 53 (2009). https://doi.org/10.1007/s00894-008-0372-2

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Keywords

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