Article

Interdisciplinary Sciences: Computational Life Sciences

, Volume 1, Issue 3, pp 214-219

Structural flexibility and interactions of PTP1B’s S-loop

  • Jing-Fang WangAffiliated withBioinformatics Center, Key Laboratory of Systems Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
  • , Ke GongAffiliated withDepartment of Bioinformatics and Biostatistics, School of Life Science and Biotechnology, Shanghai Jiao Tong University
  • , Dong-Qing WeiAffiliated withDepartment of Bioinformatics and Biostatistics, School of Life Science and Biotechnology, Shanghai Jiao Tong University Email author 
  • , Yi-Xue LiAffiliated withBioinformatics Center, Key Laboratory of Systems Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences Email author 

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Abstract

Protein-tyrosine phosphatase 1B (PTP1B) is an attractive drug target for type II diabetes and obesity. The structural motions of its S-loop play crucial roles in WPD-loop closure that is essential for the catalytic mechanism of this protein. In the current studies, totally 20 ns molecular dynamics simulations were employed on both PTP1B and its complex with inhibitors in the explicit solution surroundings with the periodic boundary conditions in order to perform detail exam on the structural flexibility of S-loop. Together with calculating RMSD values and monitoring the distances between active site and the residues in S-loop, it is found that S-loop can move towards to active site and form a tight binding pocket for substrates upon inhibitor binding. And a hydrogen bond network rearrangement was detected in this region, which may cause the transforms of both the tree-dimensional structure and the total accessible surfaces for the residues in S loop. Additionally, the second structures of Ser201 and Gly209 have huge changes for the open system, which is not detected in close system. These findings can reveal the possible mechanism of ligand recognitions and inhibitions, further providing useful information to design novel inhibitors against PTP1B and develop new treatment for type II diabetes and obesity.

Key words

protein-tyrosine phosphatase 1B type II diabetes and obesity molecular dynamics simulations essential dynamics analysis S-loop flexibility