Homology modeling and molecular dynamics study of Mycobacterium tuberculosis urease
Keywords:
Mycobacterium tuberculosis urease, three-dimensional structure, homology modeling, molecular dynamics simulationsAbstract
Introduction. M. tuberculosis urease (MTU) is an attractive target for chemotherapeutic intervention in tuberculosis by designing new safe and efficientenzyme inhibitors. A prerequisite for designing such inhibitors is an understanding of urease'sthree-dimensional (3D) structure organization. 3D structure of M. tuberculosis urease is unknown. When experimental three-dimensional structure of a protein is not known, homology modeling, the most commonly used computational structure prediction method, is the technique of choice. This paper aimed to build a 3D-structure of M. tuberculosis urease by homology modeling and to study its stability by molecular dynamics simulations. Materials and methods.To build MTU model, five high-resolution X-ray structures of bacterial ureases with three-subunit composition (2KAU, 5G4H, 4UBP, 4СEU, and 4EPB) have been selected as templates. For each template five stochastic alignments were created and for each alignment, a three-dimensional model was built. Then, each model was energy minimized and the models were ranked by quality Z-score. The MTU model with highest quality estimation amongst 25 potential models was selected. To further improve structure quality the model was refined by short molecular dynamics simulation that resulted in 20 snapshots which were rated according to their energy and the quality Z-score. The best scoring model having minimum energywas chosen as a final homology model of 3D structure forM. tuberculosis. The final model of MTU was also validated by using PDBsum and QMEAN servers.These checksconfirmed good quality of MTU homology model. Results and discussion. Homology model of MTU is a nonamer (homotrimerofheterotrimers, (αβγ)3) consisting of 2349 residues. In MTUheterotrimer, sub-units α, β, and γ tightly interact with each other at a surface of approximately 3000 Å2. Sub-unit αcontainstheenzymeactivesitewith two Ni atomscoordinated byaminoacid residues His347, His349, carbamylated Lys430*, His459, His485, Asp 573, Gly490. Helix-turn-helix motif (residues 524-545) forms a mobile flap that covers the active site and is in closed conformation impeding access to the enzyme active site. The structural stability of MTU model was checked by molecular dynamics simulation in explicit water at 300 К and рН 7,4. During the simulation, rootmeansquaredeviationsofСαatoms (RMSD Сα)and rootmeansquare fluctuations (RMSF) ofamino acid residues of MTU were monitored for 60 ns. Also, the distance between the loop that covers the active site and the dinickel center was monitored. Analysis of MD trajectory indicate that the enzyme global structure is stable and the flap covering the active center remains in closed state during the simulation time. Conclusion.Predicted three-dimensional structure of M. tuberculosis urease can be used in the studies of structure-function relationships of the enzyme, in designing new safe and efficient enzyme inhibitors aimed to struggle with infectious diseases promoted by urease activity.
References
WHO/HTM/TB2010.7 Pn. WHO Report 2010: Global Tuberculosis Control. Geneva, Switzerland: WHO Press; 2010.
Cole, S. T. Inhibiting Mycobacterium tuberculosis within and without. Phil. Trans. R. Soc. B. – 2016. – Vol. 371: 20150506.
Dixon, N. E. 1975. Jack bean urease (EC 3.5.1.5). A metalloenzyme. A simple biological role for nickel? [Text] / N. E. Dixon, C. Gazzola, R. L. Blakeley, B. Zerner. // J. Am. Chem. Soc. – 1975. – Vol. 97. – P. 4131–4133.
Ragsdale, S. W. Nickel-based enzyme systems [Text] / S.W. Ragsdale // J. Biol. Chem. – 2009. – Vol. 284, N 28. – P. 18571–18575.
Carter, E. L. Interplay of metal ions and urease [Text] / E. L. Carter, N. Flugga, J. L. Boer, S. B. Mulrooney, R. P. Hausinger // Metallomics. – 2009. – Vol. 1. – P. 207-221.
Boer, J. L. Nickel-dependent metalloenzymes [Text] / J. L. Boer, S. B. Mulrooney, R. P. Hausinger // Arch. Biochem. Biophys. – 2014. – Vol. 544. – P. 142-152.
Mobley, H. L. T. Molecular biology of microbial ureases [Text] / H. T. Mobley, M. D. Island, R. P. Hausinger // Microbiol. Rev. – 1995. – Vol. 59, N 3. - P. 451–480.
Mobley, H. L. T. Microbial ureases: significance, regulation, and molecular characterization [Text] / H. L. T. Mobley, R. P. Hausinger // Microbiol. Rev. – 1989. – Vol. 53, N 1. – P. 85–108.
Suzuki, K. Urease-producing species of intestinal anaerobes and their activities [Text] / K. Suzuki, Y. Benno, T. Mitsuoka, S. Takebe, K. Kobashi, J. Hase // Appl. Environ. Microb. - 1979. – Vol. 37, N 3. - P. 379-382.
Murchan, S. Emergence, spread, and characterization of phage variants of epidemic methicillin-resistant Staphylococcus aureus 16 in England and Wales [Text] / S. Murchan, H. M. Aucken, G. L. O’Neill,.M. Ganner, B. D. Cookson // J. Clin. Microbiol. – 2004. – Vol. 42, N 11. – P. 5154-5160.
Jin, M. Development of a large-scale HPLC-based purification for the urease from Staphylococcus leei and determination of subunit structure [Text] / M. Jin, W. Rosario, E. Watler, D.H. Calhoun // Protein Expr. Purif. – 2004. – Vol. 34, N 1. – P. 111-117.
Clemens, D. L. Purification, characterization, and genetic analysis of Mycobacterium tuberculosis urease, a potentially critical determinant of host-pathogen interaction [Text] / D. L. Clemens, B.-Y. Lee, M. A. Horwitz // J. Bacteriol. – 1995. – Vol. 177, N 19. – P. 5644-5652.
Dupuy, B. Clostridium perfringens urease genes are plasmid borne [Text] / B. Dupuy, G. Daube, M. R. Popoff, S. T. Cole // Infect. Immun. – 1997. – Vol. 65, N 6. – P. 2313-2320.
Futagami, S. Systemic and local immune responses against Helicobacter pylori urease in patients with chronic gastritis: distinct IgA and IgG productive sites [Text] / S. Futagami, H. Takahashi, Y. Norose, M. Kobayashi, M. // Gut. – 1998. – Vol. 43, N 2. – P. 168-175.
Nakano, M. Association of the urease gene with enterohemorrhagic Escherichia coli strains irrespective of their serogroups [Text] / M. Nakano, T. Iida, M. Ohnishi, K. Kurokawa, A. Takahashi, T. Tsukamoto, T. Yasunaga, T. Hayashi, T. Honda // J. Clin. Microbiol. – 2001. – Vol. 39, N 12. – P. 4541-4543.
Orth, D. Prevalence, structure and expression of urease genes in Shiga toxin-producing Escherichia coli from humans and the environment [Text] / D. Orth, K. Grif, M. P. Dierich, R. Wurzner // Int. J. Hyg. Environ.-Health. – 2006. – Vol. 209, N 6. – P. 513-520.
Konieczna, I. Bacterial ureases and its role in long-lasting human diseases [Text] / I. Konieczna, P. Zarnowiec, M. Kwinkowski, et al. // Curr. Protein. Pept. Sci. – 2012. – Vol. 13. – P. 789-806.
Tange, Y. Identification of the ure1+ gene encoding urease in fission yeast [Text] / Y. Tange, O. Niwa // Curr. Genet. – 1997. – Vol. 32, N 3. – P. 244-246.
Sirko, A. Plant ureases: roles and regulation [Text] / A. Sirko, R. Brodzik // Acta Biochim. Pol. – 2000. – Vol. 47, N 4. – P. 1189-1195.
Zonia, L. E. Essential role of urease in germination of nitrogen-limited Arabidopsis thaliana seeds [Text] / L. E. Zonia, N. E. Stebbins, J. C. Polacco // Plant Physiol. – 1995. – Vol. 107, N 4. – P. 1097-1103.
Pedrozo, H. A. A mechanism of adaptation to hypergravity in the statocyst of Aplysia californica [Text] / H. A. Pedrozo, Z. Schwartz, M. Luther, D. D. Dean, B. D. Boyan, M. L. Wiederhold // Hear Res. – 1996. – Vol. 102, N 1-2. – P. 51-62.
McLean, R. J. C. The ecology and pathogenicity of urease-producing bacteria in the urinary tract [Text] / R. J. C. McLean, J. C. Nickel, K.-J. Cheng, J. W. Costerton // CRC Crit. Rev. Microbiol. – 1988. – Vol. 16, N 1. – P. 37–79.
Burne, R. A. Bacterial ureases in infectious diseases [Text] / R. A. Burne, Y.-Y. M. Chen // Microbes and Infection. – 2000. – Vol. 2. – P. 533−542.
Collins, C. M. Bacterial ureases: structure, regulation of expression and role in pathogenesis [Text] / M. Collins and S. E. F. D’Orazio // Mol. Microbiol. – 1993. – Vol. 9, N 5. P. 907–913.
Follmer, C. Ureases as a target for the treatment of gastric and urinary infections [Text] / C. Folmer // J. Clin. Pathol. – 2010. – Vol. 63, N 5. – P. 424-430.
Modolo, L. V. An overview on the potential of natural products as urease inhibitors: a review [Text] / L. V. Modolo, A. X. de Souza, L. P. Horta, D. P. Araujo, A. de Fatima // J. Adv. Res. – 2015. – Vol. 6. – P. 35-44.
Kosikowska, P. Urease inhibitors as potential drugs for gastric and urinary tract infections: a patent review [Text] / P. Kosikowska, L. Berlicki // Expert Opin. Ther. Pat. – 2011. – Vol. 21. – P. 945-957.
Berlicki, Ł. N-substituted aminomethanephosphonic and aminomethane-P-methylphosphinic acids as inhibitors of ureases [Text] / Ł. Berlicki, M. Bochno, A. Grabowiecka, A. Białas, et al. // Amino Acids. – 2012. – Vol. 42. – P.1937–1945.
Xiao, Z.-P. Molecular docking, kinetic study, and structure-activity relationship analysis of quercetin and its analogous as Helicobacter pylori urease inhibitors [Text] / Z.-P. Xiao, X.-D. Wang, Z.-Y. Peng, S. Huang, et al. // Agricult. Food Chem. – 2012. – Vol. 60. – P. 10572-10577.
Cun, S.-J. Urease inactivation by an unusual GroES chaperonin [Text] / S.-J. Cun, H.-Z. Sun // Science China Chemistry. – 2014. – Vol. 57, N 6. – P.842–848.
Hassan, S. T. S. Plant-derived urease inhibitors as alternative chemotherapeutic agents [Text] / S. T. S. Hassan, M. Zemlicka // Arch. Pharm. Chem. Life Sci. – 2016. Vol. 349. – P. 1–16.
Xiao, Z.-P. Synthesis and evaluation of N-analogs of 1,2-diarylethane as Helicobacter pylori urease inhibitors [Text] / Z.-P. Xiao, W.-K. Shi, P.-F. Wang, W. Wei, et al. // Bioorganic and Medicinal Chemistry. – 2015. – Vol. 23. – P. 4508–4513.
Mazzei, L. Inactivation of urease by 1,4-benzoquinone: chemistry at the protein surface [Text] / L. Mazzei, M. Cianci, F. Musiani, S. Ciurli // Dalton Trans. – 2016. – Vol. 45. – P. 5455-5459.
Mazzei, L. Inactivation of urease by catechol: kinetics and structure [Text] / L. Mazzei, M. Cianci, F. Musiani, G. Lente, et al. // J. Inorg. Biochem. – 2017. – Vol.166. – P. 182-189.
Zambelli, B. Chemistry of Ni2+ in urease: Sensing, trafficking, and catalysis [Text] / D. Zambelli, F. Musiani, S. Benini, S. Ciurli // Accounts Chem. Res. – 2011. – Vol. 44. – P. 520-530.
Balasubramanian, A. Crystal structure of the first plant urease from jack bean: 83 years of journey from its first crystal to molecular structure [Text] / A. Balasubramanian, K, Ponnuraj // J. Mol. Biol. – 2010. Vol. 400. – P. 274–283.
Jabri, E. The crystal structure of urease from Klebsiella aerogenes [Text] / E. Jabri, M. B. Carr, R. P. Hausinger, P. A. Karplus // Science. – 1995. – Vol. 268, N 5213. – P. 998-1004.
Karplus, P.A. 70 years of crystalline urease: what have we learned? [Text] / P. A. Karplus, M. F. Pearson, R. P. Hausinger // Acc. Chem. Res. – 1997. – Vol. 30. – P. 330-337.
Ha, N.-C. Supramolecular assembly and acid resistance of Helicobacter pylori urease [Text] / N.-C. Ha, S.-T. Oh, J. Y. Sung, et al. // Nature Struct. Biol. - 2001. – Vol. 8. – P. 505-509.
Benini, S. A new proposal for urease mechanism based on the crystal structures of the native and inhibited enzyme from Bacillus pasteurii: why urea hydrolysis costs two nickels? [Text] / S. Benini, W. R. Rypniewski, K. S. Wilson, S. Miletti, et al. // Structure. – 1999. – Vol. 7, N 2. – P. 205-216.
Habel, J. E. Structure of Rv1848 (UreA), the Mycobacterium tuberculosis urease gamma subunit [Text] / J. E. Habel, E. H. Bursey, B. S. Rho, et al. // Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. – 2010. – Vol. 66, N 7. – P. 781-786.
Venselaar, H. Homology modelling and spectroscopy, a never-ended love story [Text] / H. Venselaar, R. P. Joosten, B. Vroling, C. A. B. Baakman, et al. // Eur. Biophys. J. – 2010. – Vol. 39. – P. 551-563.
Masini, T. Validation of a homology model of Mycobacterium tuberculosis DXS: rationalization of observed activities of thiamine derivatives as potent inhibitors of two orthologues of DXS [Text] / T. Masini, B. Lacy, L. Monjas, D. Hawksley, et al. // Org. Biol. chem. – 2015. – Vol. 13. – P. 11263-11277.
Ganguly, B. Homology modeling, functional annotation and comparative genomics of outer membrane protein H of Pasteurella multocida [Text] / B. Ganguly, K. Tewari, R. Singh // Journal of Theoretical Biology. – 2015. – Vol. 386. – P. 18-24.
Benson, D. A. GenBank [Text] / D. A. Benson, I. Karsch-Mizrachi, D. J. Lipman, J. Ostell, D. L. Wheeler // Nucl. Acids Res. – 2007. – Vol. 35, Suppl 1. – P. D21-D25.
Altschul, S. F. Basic local alignment search tool [Text] / S. F. Altschul, W. Gish, W. Miller, E. W. Myers, D. J. Lipman // J. Mol. Biol. – 1990. – Vol. 215. - P. 403-410.
Altschul, S. F. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs [Text] / S. F. Altschul, T. L. Madden, A. A. Schaeffer, J. Zhang, Z. Zhang, W. Miller, D. J. Lipman // Nucleic Acids Res. – 1997. – Vol. 25. - P. 3389-3402.
Rose, P. W. The RCSB protein data bank: integrative view of protein, gene and 3D structural information [Text] / P. W. Rose, A. Prlić, A. Altunkaya, C. Bi et al. // Nucleic Acids Research. – 2017. – Vol. 45. – P. D271-D281.
Hooft, R. W. W. Errors in protein structure [Text] / R. W. W. Hooft, G. Vriend, C. Sander, E. E. Abola // Nature. – 1996. – Vol. 381, N 6580. – P. 272-272.
Hooft, R. W. W. The PDBFINDER database: A summary of PDB, DSSP and HSSP information with added value [Text] / R. W. W.
Hooft, C. Sander, G. Vriend G. // CABIOS/Bioinformatics. – 1996. – Vol. 12. – P.
-529.
Mueckstein, U. Stochastic pairwise alignments [Text] / U. Mueckstein, I. L. Hofacker, P. F. Stadler // Bioinformatics. – 2002. – Vol. 18, Sup. 2. – P. 153-160.
Qiu, J. SSALN: an alignment algorithm using structure dependent substitution matrices and gap penalties learned from structurally aligned protein pairs [Text] / J. Qiu, R. Elber // Proteins. – 2006. – Vol. 62. – P. 881–891.
Canutescu, A. A. Cyclic coordinate descent: A robotics algorithm for protein loop closure [Text] / A. A. Canutescu, R. L. Jr. Dunbrack // Protein Sci. – 2003. – Vol. 12. – P. 963-972.
Canutescu, A. A. A graph-theory algorithm for rapid protein side-chain prediction [Text] / A. A. Canutescu, A. A. Shelenkov, R. L. Jr. Dunbrack // Protein Sci. – 2003. – Vol. 12. – P. 2001-2014.
Krieger, E. Assignment of protonation states in proteins and ligands: combining pKa prediction with hydrogen bonding network optimization [Text] / E. Krieger, R. L. Dunbrack, R. W. Hooft, B. Krieger // Methods Mol. Biol. – 2012. – Vol. 819. – P. 405-421.
Kreiger, E. Improving physical realism, stereochemistry, and side-chain accuracy in homology modelling: four approaches that perfomed well in CASP8 [Text] / E. Kreiger, K. Joo, J. Lee, et al. // Proteins. – 2009. – Vol. 77, Suppl. 9. – P. 114-122.
Krieger, E. Making optimal use of empirical energy functions: force field parameterization in crystal space [Text] / E. Krieger, T. Darden, S. Nabuurs, et al. // Proteins. – 2004. – Vol. 57. – P. 678-683.
Krieger, E. Increasing the precision of comparative models with YASARA NOVA - a self-parameterizing force field [Text] / E. Krieger, G. Koraimann, G. Vriend // Proteins. – 2002. – Vol. 47. – P. 393-402.
Krieger, E. Fast empirical pKa prediction by Ewald summation [Text] / E. Krieger, J. E. Nielsen, C. A. Spronk, G. Vriend // J. Mol. Graph. Model. – 2006. – Vol. 25, N 4. – P. 481-486.
Krieger, E. YASARA View - molecular graphics for all devices - from smartphones to workstations [Text] / E. Krieger, G. Vriend // Bioinformatics. – 2014. – Vol. 30. – P. 2981-2982.
Krieger, E. New ways to boost molecular dynamics simulations [Text] / E. Krieger, G. Vriend // J.Comput.Chem. – 2015. – Vol.36. – P. 996-1007.
Benkert, P. QMEAN: A comprehensive scoring function for model quality assessment [Text] / P. Benkert, S. C. E. Tosatto, D. Schomburg // Proteins: Structure, Function, and Bioinformatics. - 2008. – Vol. 71, N 1. – P. 261-277.
Benkert, P. Towards the estimation of the absolute quality of individual protein structure model [Text] / P. Benkert, M. Basiani, T. Schwede // Bioinformatics. - 2011. – Vol. 27, N 3. – P. 343-350.
Benkert, P. QMEAN server for protein model quality estimation [Text] / P. Benkert, M. Kuenzli, T. Schwede // Nucleic Acids Res. – 2009. – Vol. 37. – P. W510-514.
Laskowski, R. A. Enhancing the functional annotation of PDB structures in PDBsum using key figures extracted from the literature [Text] / R. A. Laskowski // Bioinformatics. – 2007. – Vol. 23. – P. 1824-1827.
Laskowski, R. A. PDBsum: summaries and analyses of PDB structures [Text] / R. A. Laskowski // Nucleic Acids Res. – 2001. – Vol. 29. – P. 221-222.
Laskowski, R. A. PDBsum more: new summaries and analyses of the known 3D structures of proteins and nucleic acids [Text] / R. A. Laskowski, V. V. Chistyakov, J. M. Thornton // Nucleic Acids Res. – 2005. – Vol. 33. – P. D266-D268.
Laskowski, R. A. PDBsum new things [Text] / R. A. Laskowski // Nucleic Acids Res. – 2009. – Vol. 37. – P. D355-D359.
Wallace, A. C. LIGPLOT: a program to generate schematic diagrams of protein-ligand interactions [Text] / A. C. Wallace, R. A. Laskowski, J. M. Thornton // Protein Eng. – 1996. – Vol. 8. – P. 127-134.
de Beer, T. A. P. PDBsum additions [Text] / T. A. P. de Beer, K. Berka, J. M. Thornton, R. A. Laskowski // Nucleic Acids Res. – 2014. – Vol. 42. - P. D292-D296.
Krissinel, E. Inference of macromolecular assemblies from crystalline state [Text] / E. Krissinel, K. Henrick // J. Mol. Biol. – 2007. – Vol. 372. – P. 774-797.
Hornak, V. Comparison of multiple AMBER force field and development of improved protein backbone parameters [Text] / V. Hornak, R. Abel, A. Okur, B. Strockbine, et al. // Proteins. – 2006. – Vol. 65. – P. 712-725.
Essman, U. A smooth particle mesh Ewald method [Text] / U. Essman, L. Perera, M. L. Berkowitz, et al. // J. Chem. Phys. B. – 1995. – Vol. 103. – P. 8577-8593.
Farrugia, M. A. Analysis of a soluble (UreD:UreF:UreG)2 accessory protein complex and its interactions with Klebsiella aerogenes urease by Mass Spectrometry [Text] / M. A. Farrugia1, L. Han, Y. Zhong, J. L. Boer, B. T. Ruotolo, R. P. Hausinger // J. Am. Soc. Mass. Spectrom. – 2013. – Vol. 24, N 9. – P. 1328–1337.
Ligabue-Braun, R. Evidence-based docking of the urease activation complex [Text] / R. Ligabue-Braun, R. Real-Guerra, C. R. Carlini, H. Verli // J. Biomol. Struct. Dyn. – 2013. - Vol. 31, N 8. – P. 854–861.
Quiroz-Valenzuela, S. The structure of urease activation complexes examined by flexibility analysis, mutagenesis, and small-angle X-ray scattering./ S. Quiroz-Valenzuela, S. C. Sukuru, R. P. Hausinger, L. A. Kuhn, W. T. Heller // Arch. Biochem. Biophys. – 2008. – Vol. 480, 51–57.
Fong, Y. H. Structure of UreG/UreF/UreH complex reveals how urease accessory proteins facilitate maturation of Helicobacter pylori urease [Text] / Y. H. Fong, H. C. Wonh, M. H. Yuen, P. H. Lau et al. // PLoS Biol. – 2013. – Vol. 11, N 10. – P. 1-16.
Lv, J. Structural and functional role of nickel ions in urease by molecular dynamics simulations [Text] / J. Lv, Y. Jiang, Q. Yu. // J. Biol. Inorg. Chem. – 2011. – Vol. 16. – P. 125-135.
Roberts, B. P. Wide-open flaps are key to urease activity [Text] / B. P. Roberts, B. R. Miller, A. E. Roitberg, R. M. Merz // J. Am. Chem. Soc. – 2012. – Vol. 134. – P. 9934–9937.
Macomber, L. Reduction urease activity by interaction with the flap covering the active site [Text] / L. Macomber, M. S. Minkara, R. P. Hausinger, K. M. Merz // J. Chem. Inf. Model. – 2015. – Vol. 55, N 2. – P. 354-361.
Minkara, M. S. Molecular dynamics study of Helicobacter pylori urease [Text] / M. S. Minkara, M. N. Ucisik, M. N. Weaver, K. M. Merz, Jr. // J. Chem. Theory Comput. – 2014. – Vol. 10. – P. 1852-1862.
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