Structural flexibility and interactions of PTP1B’s S-loop

Article

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 

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References

  1. [1]
    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
  2. [2]
    Barford, D., Flint, A.J., Tonks, N.K. 1994. Crystal structure of human protein tyrosine phosphatase 1B. Science 263, 1397–1404.CrossRefPubMedGoogle Scholar
  3. [3]
    Berendsen, H.J.C., van der Spoel, D., van Drunen R. 1995. GROMACS: a message-passing parallel molecular dynamics implementation. Comp Phys Commun 91, 43–56.CrossRefGoogle Scholar
  4. [4]
    Berman, H.M., Westbrook, J., Feng, Z., Gilliland, G., Bhat T.N., Weissig, H., Shindyalov, I.N., Bourne, P.E. 2000. The protein data bank. Nucleic Acids Res 28, 235–242.CrossRefPubMedGoogle Scholar
  5. [5]
    Cheng, A., Tremblay, M.L. 2004. Insulin receptor PTP: PTP1B. Handb Cell Signal 1, 729–732.CrossRefGoogle Scholar
  6. [6]
    Cook, W.S., Unger, R.H. 2002. Protein tyrosine phosphatase 1B: A potential leptin resistance factor of obesity. Dev Cell 2, 385–387.CrossRefPubMedGoogle Scholar
  7. [7]
    Darden, T., York, D., Pedersen, L. 1993. Particel mesh Ewald: an N-log(N) method for Ewald sums in large systems. J Chem Phys 98, 10089–10092.CrossRefGoogle Scholar
  8. [8]
    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
  9. [9]
    Gum, R.J., Gaede, L.L., Koterski, S.L., Heindel, M., Clampit, J.E., Zinker, B.A., Trevillyan, J.M., Ulrich, R.G., Jirousek, M.R., Rondinone, C.M. 2003. Reduction of protein tyrosine phosphatase 1B increases insulin-dependent signaling in ob/ob mice. Diabetes 52, 21–28.CrossRefPubMedGoogle Scholar
  10. [10]
    Hess, B. 2000. Similarities between principal components of protein dynamics and random diffusion. Phys Rev E 62, 8438–8448.CrossRefGoogle Scholar
  11. [11]
    Hunter, T. 1995. Protein kinases and phosphatase: the Yin and Yang of protein phosphorylation and signalling. Cell 80, 225–236.CrossRefPubMedGoogle Scholar
  12. [12]
    Jia, Z., Barford, D., Flint, A.J., Tonks, N.K. 1995. Structural basis for phosphotyrosine peptide recognition by protein tyrosine phosphatase 1B. Science 268, 1754–1758.CrossRefPubMedGoogle Scholar
  13. [13]
    Johnson, T.O., Ermolieff, J., Jirousek, M.R. 2002. Protein tyrosine phosphatase 1B inhibitors for diabetes. Nat Rev Drug Discov 1, 696–708.CrossRefPubMedGoogle Scholar
  14. [14]
    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
  15. [15]
    Kolmodin, K., Agvist, J. 2001. The catalytic mechanism of protein tyrosine phosphatases revisited. FEBS Lett 498, 208–213.CrossRefPubMedGoogle Scholar
  16. [16]
    Liu, G.X., Tan, J.Z., Niu, C.Y., Shen, J.H., Luo, X.M., Shen, X., Chen, K.X., Jiang, H.L. 2006. Molecular dynamics simulations of interaction between proteintyrosine phosphatase 1B and a bidentate inhibitor. Acta Pharm Sin 27, 100–110.CrossRefGoogle Scholar
  17. [17]
    Pedersen, A.K., Peters, G.H., Moller, K.B., Iversen, L.F., Kastrup, J.S. 2004. Water-molecule network and active-site flexibility of apo protein tyrosine phosphatase 1B. Acta Crystallogr Sect D 60, 1527–1534.CrossRefGoogle Scholar
  18. [18]
    Peters, G.H., Frimurer, T.M., Andersen, J.N., Olsen, O.H. 2000. Molecular dynamics simulations of proteintyrosine phosphatase 1B. II. Substrate-enzyme interactions and dyanmics. Biophys J 78, 2191–2200.CrossRefPubMedGoogle Scholar
  19. [19]
    Stone, R.L., Dixon, J.E. 1994. Protein tyrosine phosphatases. J Biol Chem 269, 31323–31326.PubMedGoogle Scholar
  20. [20]
    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
  21. [21]
    Van Aalten, D.M.F., Bywater, R., Findlay, J.B., Hendlich, M., Hooft, R.W., Vriend, G. 1996. PRODRG: a program for generating molecular topologies and unique molecular descriptors from coordinates of small molecules. J Comput Aided Mol Des 10, 255–262.CrossRefPubMedGoogle Scholar
  22. [22]
    Van Aalten, D.M.F., De Groot, B.L., Findlay, J.B.C., Berendsen, H.J.C., Amadei, A. 1997. A comparison of techniques for calculating protein essential dyanmics. J Comput Chem 18, 169–181.CrossRefGoogle Scholar
  23. [23]
    Wang, J.F., Wei, D.Q., Chen, C., Li, Y.X., Chou, K.C. 2008. Molecular modeling of two CYP2C19 SNPs and its implications for personalized drug design. Protein Pept Lett 15, 27–32.CrossRefPubMedGoogle Scholar
  24. [24]
    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
  25. [25]
    Wang, J.F., Wei, D.Q., Li, L., Zheng, S.Y., Li, Y.X., Chou, K.C. 2007. 3D structure modeling of cytochrome P450 2C19 and its implication for personalized drug design. Biochem Biophys Res Commun 355, 513–519.CrossRefPubMedGoogle Scholar
  26. [26]
    Wang, J.F., Wei, D.Q., Lin, Y., Du, H.L., Li, Y.X., Chou, K.C. 2007. Insights from modeling the 3D structure of NAD(P)H-dependent D-xylose reductase of Pichia stipitis and its binding interactions with NAD and NADP. Biochem Biophys Res Commun 359, 323–329.CrossRefPubMedGoogle Scholar
  27. [27]
    Wiesmann, C., Barr, K.J., Kung, J., Zhu, J., Erlanson, D.A., Shen, W., Fahr, B.J., Zhong, M., Taylor, L., Randall, M., McDowell, R.S., Hansen, S.K. 2004. Allosteric inhibition of protein tyrosine phosphatase 1B. Nat Struct Mol Biol 11, 730–737.CrossRefPubMedGoogle Scholar
  28. [28]
    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
  29. [29]
    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

Copyright information

© International Association of Scientists in the Interdisciplinary Areas and Springer-Verlag GmbH 2009

Authors and Affiliations

  1. 1.Bioinformatics Center, Key Laboratory of Systems Biology, Shanghai Institutes for Biological SciencesChinese Academy of SciencesShanghaiChina
  2. 2.Department of Bioinformatics and Biostatistics, School of Life Science and BiotechnologyShanghai Jiao Tong UniversityShanghaiChina

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