Structural flexibility and interactions of PTP1B's S-loop.
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.
Wang
Jing-Fang
JF
Bioinformatics Center, Key Laboratory of Systems Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.
Gong
Ke
K
Wei
Dong-Qing
DQ
Li
Yi-Xue
YX
D000465:Algorithms; D000818:Animals; D001671:Biochemistry / Q000379:methods; D020134:Catalytic Domain; D019295:Computational Biology / Q000379:methods; D003198:Computer Simulation; D018360:Crystallography, X-Ray / Q000379:methods; D006801:Humans; D007477:Ions; D008968:Molecular Conformation; D025341:Principal Component Analysis; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000737:chemistry*; D012984:Software; D013997:Time Factors
D007477:Ions; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1