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The study of the role of mutations M182T and Q39K in the TEM-72 β-lactamase structure by the molecular dynamics method

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Abstract

Synthesis of β-lactamases is one of the common mechanisms of bacterial resistance to β-lactam antibiotics such as penicillins and cephalosporins. The widespread use of antibiotics resulted in appearance of numerous extended-spectrum β-lactamase variants or inhibitor-resistant β-lactamases. In TEM type β-lactamases mutations of 92 residues have been described. Several mutations are functionally important and they determine the extended substrate specificity. However, roles of the most so-called associated mutations, located far from the active site, remain unknown. We have investigated the role of associated mutations in structure of β-lactamase TEM-72, which contains two key mutations (G238S, E240K) and two associated mutations (Q39K, M182T) by means of molecular dynamics simulation. Appearance of the key mutations (in 238 and 240 positions) caused destabilization of the protein globule, characterized by increased mobility of amino acid residues. Associated mutations (Q39K, M182T) exhibited opposite effect on the protein structure. The mutation M182T stabilized, while the mutation Q39K destabilized the protein. It appears that the latter mutation promoted optimization of the conformational mobility of β-lactamase and may influence the enzyme activity.

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References

  1. Tipper, D.J. and Strominger, J.L., Proc. Natl. Acad. Sci. USA, 1965, vol. 54, pp. 1133–1141.

    Article  CAS  Google Scholar 

  2. Ambler, R.P., Philos. Trans. R. Soc. Lond. B, 1980, vol. 289, pp. 321–331.

    Article  CAS  Google Scholar 

  3. Bush, K., Ann. N.Y. Acad. Sci., 2013, vol. 1277, pp. 84–90.

    Article  CAS  Google Scholar 

  4. Livermore, D.M., Korean J. Int. Med., 2012, vol. 27, pp. 128–142.

    Article  CAS  Google Scholar 

  5. Rubtsova, M.Y., Ulyashova, M.M., Bachmann, T.T., Schmid, R.D., and Egorov, AM., Usp. Sovr. Biol., 2010, vol. 50, pp. 303–348.

    CAS  Google Scholar 

  6. Tang, S.S., Apisarnthanarak, A., and Hsu, L.Y., Adv. Drug Deliv. Rev., 2014, vol. 78, pp. 3–13.

    Article  CAS  Google Scholar 

  7. Frere, J.M. and Joris, B., CRC Crit. Rev. Microbiol., 1985, vol. 11, pp. 299–396.

    Article  CAS  Google Scholar 

  8. Medeiros, A.A., Clin. Infect. Dis., 1997, vol. 24, pp. S19–S45.

    Article  CAS  Google Scholar 

  9. Matagne, A., Lamotte-Brasseur, J., and Frere, J.M., Biochem. J., 1998, vol. 330, pp. 581–598.

    Article  CAS  Google Scholar 

  10. http://www.lahey.org/studies.

  11. Pimenta, A.C., Fernandes, R., and Moreira, I.S., Mini Rev. Med. Chem., 2014, vol. 14, pp. 111–122.

    Article  CAS  Google Scholar 

  12. Fisher, J.F., Meroueh, S.O., and Mobashery, S., Chem. Rev., 2005, vol. 105, pp. 395–424.

    Article  CAS  Google Scholar 

  13. Huang, W. and Palzkill, T., Proc. Natl. Acad. Sci. USA, 1997, vol. 94, pp. 8801–8806.

    Article  CAS  Google Scholar 

  14. Farzaneh, S., Chaibi, E.B., Peduzzi, J., Barthelemy, M., Labia, R., Blazquez, J., and Baquero, F., Antimicrob. Agents Chemother., 1996, vol. 40, pp. 2434–2436.

    CAS  Google Scholar 

  15. Sideraki, V., Huang, W., Palzkill, T., and Gilbert, H.F., Proc. Natl. Acad. Sci. USA, 2001, vol. 98, pp. 283–288.

    CAS  Google Scholar 

  16. Giampaolo, A.D., Mazza, F., Daidone, I., Amicosante, G., Perilli, M., and Aschi, M., Biochem. Biophys. Res. Commun., 2013, vol. 436, pp. 666–671.

    Article  Google Scholar 

  17. Baig, M.H., Sudhakar, D.R., Kalaiarasan, P., Subbarao, N., Wadhawa, G., Lohani, M., Khan, M.K., and Khan, A.U., PLoS One, 2014, vol. 9, e112456.

    Article  Google Scholar 

  18. Stec, B., Holtz, K.M., Wojciechowski, C.L., and Kantrowitz, E.R., Acta Crystallogr. Sect. D. Biol. Crystallogr., 2005, vol. 61, pp. 1072–1079.

    Article  Google Scholar 

  19. Docquier, J.D., Benvenuti, M., Calderone, V., Rossolini, G.M., and Mangani, S., Acta Crystallogr Sect. F. Struct. Biol. Cryst. Commun., 2011, vol. 67, pp. 303–306.

    Article  CAS  Google Scholar 

  20. Brown, N.G., Pennington, J.M., Huang, W., Ayvaz, T., and Palzkill, T., J. Mol. Biol., 2010, vol. 404, pp. 832–846.

    Article  CAS  Google Scholar 

  21. Fisette, O., Morin, S., Savard, P.-Y., Lague, P., and Gagne, S.M., Biophys. J., 2010, vol. 98, pp. 637–645.

    Article  CAS  Google Scholar 

  22. Fisette, O., Gagne, S., and Lague, P., Biophys. J., 2012, vol. 103, pp. 1790–1801.

    Article  CAS  Google Scholar 

  23. Roccatano, D., Sbardella, G., Aschi, M., Amicosante, G., Bossa, C., Di Nola, A., and Mazza, F., J. Comput.-Aided Mol. Des., 2005, vol. 19, pp. 329–340.

    Article  CAS  Google Scholar 

  24. Paterson, D.L. and Bonomo, R.A., Clin. Microbiol. Rev., 2005, vol. 18, pp. 657–686.

    Article  CAS  Google Scholar 

  25. Wang, X., Minasov, G., and Shoichet, B.K., J. Mol. Biol., 2002, vol. 320, pp. 85–95.

    Article  CAS  Google Scholar 

  26. Mitraki, A., Fane, B., Haase-Pettingell, C., Sturtevant, J., and King, J., Science, 1991, vol. 253, pp. 54–58.

    Article  CAS  Google Scholar 

  27. Shortle, D. and Lin, B., Genetics, 1985, vol. 110, pp. 539–555.

    CAS  Google Scholar 

  28. Marciano, D.C., Pennington, J.M., Wang, X., Wang, J., Chen, Y., Thomas, V.L., Shoichet, B.K., and Palzkill, T., J. Mol. Biol., 2008, vol. 384, pp. 151–164.

    Article  CAS  Google Scholar 

  29. Bradford, P.A., Clin. Microbiol. Rev., 2001, vol. 14, pp. 933–951.

    Article  CAS  Google Scholar 

  30. Hardy, L.W. and Kirsch, J.F., Biochemistry, 1984, vol. 23, pp. 1275–1282.

    Article  CAS  Google Scholar 

  31. Palzkill, T., Le, Q.-Q., Venkatachalam, K.V., LaRocco, M., and Ocera, H., Mol. Microbiol., 1994, vol. 12, pp. 217–229.

    Article  CAS  Google Scholar 

  32. Vakulenko, S.B., Toth, M., Taibi, P., Mobashery, S., and Lerner, S., Antimicrob. Agents Chemother., 1995, vol. 39, pp. 1878–1880.

    Article  CAS  Google Scholar 

  33. Petrosino, J.F. and Palzkill, T., J. Bacteriol., 1996, vol. 178, pp. 1821–1828.

    Article  CAS  Google Scholar 

  34. Delmas, J., Robin, F., Bittar, F., Chanal, C., and Bonnet, R., Antimicrob. Agents Chemother., 2005, vol. 49, pp. 4280–4287.

    Article  CAS  Google Scholar 

  35. Stojanoski, V., Chow, D.-C., Hu, L., Sankaran, B., Gilbert, H.F., Prasad, B.V., and Palzkill, T., J. Biol. Chem., 2015, vol. 290, pp. 10382–10394.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Institute of Biomedical Chemistry, ul. Pogodinskaya 10, Moscow, 119121, Russia

    D. S. Shcherbinin & A. V. Veselovsky

  2. Lomonosov Moscow State University, Vorobievy Gory, 1, bld. 3, Moscow, Russia

    M. Yu. Rubtsova, V. G. Grigorenko, I. V. Uporov & A. M. Egorov

Authors
  1. D. S. Shcherbinin
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  2. M. Yu. Rubtsova
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  3. V. G. Grigorenko
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  4. I. V. Uporov
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  5. A. V. Veselovsky
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  6. A. M. Egorov
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Correspondence to A. V. Veselovsky.

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Original Russian Text © D.S. Shcherbinin, M.Yu. Rubtsova, V.G. Grigorenko, I.V. Uporov, A.V. Veselovsky, A.M. Egorov, 2017, published in Biomeditsinskaya Khimiya.

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Shcherbinin, D.S., Rubtsova, M.Y., Grigorenko, V.G. et al. The study of the role of mutations M182T and Q39K in the TEM-72 β-lactamase structure by the molecular dynamics method. Biochem. Moscow Suppl. Ser. B 11, 120–127 (2017). https://doi.org/10.1134/S1990750817020056

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  • DOI: https://doi.org/10.1134/S1990750817020056

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