Structural flexibility and interactions of PTP1B’s S-loop
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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 wordsprotein-tyrosine phosphatase 1B type II diabetes and obesity molecular dynamics simulations essential dynamics analysis S-loop flexibility
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- Appiah, E.A., Kennedy B.P. 2003. Protein tyrosine phosphatase: The quest for negative regulators of insulin action. Am J Physiol 84, E663–E670.Google Scholar
- Elchebly, M., Payette, P., Michaliszyn, E., Cromlish, W., Collins, S., Loy, A.L., Normandin, D., Cheng, A., Hagen, J.H., Chan, C.C., Ramachandran, C., Gresser, M.J., Tremblay, M.L., Kennedy, B.P. 1999. Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase 1B gene. Science 283, 1544–1548.CrossRefPubMedGoogle Scholar
- Klaman, L.D., Boss, O., Peroni, O.D., Kim, J.K., Martino, J.L., Zabolotny, J.M., Moghal, N., Lubkin, M., Kim, Y.B., Sharpe, A.H., Krongrad, A.S., Shulman, G.I., Neel, B.G., Kahn, B.B. 2000. Increased energy expenditure, decreased adiposity, and tissue-specific insulin sensitivity in protein-tyrosine phosphatase 1Bdeficient mice. Mol Cell Biol 20, 5479–5489.CrossRefPubMedGoogle Scholar
- Tonks, N.K., Diltz, C.D., Fischer, E.H. 1988. Purification of the major protein tyrosine phosphatases of human placenta. J Biol Chem 263, 6715–6721.Google Scholar
- Wang, J.F., Wei, D.Q., Du, H.L., Li, Y.X., Chou, K.C. 2008. Molecular modeling studies on NADP-dependent of Candida tropicallis strain xylose reductase. Open Bioinformatics J 2, 89–96.Google Scholar
- Wilson, D.P., Wan, Z.K., Xu, W.X., Kirincich, S.J., Follows, B.C., McCarthy, D.J., Foreman, K., Moretto, A., Wu, J.J., Zhu, M., Binnun, E., Zhang, Y.L., Tam, M., Erbe, D.V., Tobin, J., Xu, X., Leung, L., Shilling, A., Tam, S.Y., Mansour, T.S., Lee, J. 2007. Structurebased optimization of protein tyrosine phosphatase 1B inhibitors: From the active site to the second phosphotyrosine binding site. J Med Chem 50, 4681–4698.CrossRefPubMedGoogle Scholar
- Zinker, B.A., Rondinone, C.M., Trevillan, J.M., Gum, R.J., Clampit, J.E., Waring, J.F., Xie, N., Wilcox, D., Jacobson, P., Frost, L., Kroeger, P.E., Reilly, R.M., Koterski, S., Opgenorth, T.J., Ulrich, R.G., Rosby, S., Butler, M., Murray, S.F., McKay, R.A., Bhanot, S., Monia, B.P., Jirousek, M.R. 2002. PTP1B antisense oligo-nucleotide lowers PTP1B protein, normalizesblood glucose, and improves insulin sensitivity in dibetic mice. Proc Natl Acad Sci USA 99, 11357–11362.CrossRefPubMedGoogle Scholar