Skip to main content
SpringerLink
Log in

Mycobacterium tuberculosis serine/threonine protein kinases: structural information for the design of their specific ATP-competitive inhibitors

  • Published:
Journal of Computer-Aided Molecular Design Aims and scope Submit manuscript

Abstract

In the last decades, human protein kinases (PKs) have been relevant as targets in the development of novel therapies against many diseases, but the study of Mycobacterium tuberculosis PKs (MTPKs) involved in tuberculosis pathogenesis began much later and has not yet reached an advanced stage of development. To increase knowledge of these enzymes, in this work we studied the structural features of MTPKs, with focus on their ATP-binding sites and their interactions with inhibitors. PknA, PknB, and PknG are the most studied MTPKs, which were previously crystallized; ATP-competitive inhibitors have been designed against them in the last decade. In the current work, reported PknA, PknB, and PknG inhibitors were extracted from literature and their orientations inside the ATP-binding site were proposed by using docking method. With this information, interaction fingerprints were elaborated, which reveal the more relevant residues for establishing chemical interactions with inhibitors. The non-crystallized MTPKs PknD, PknF, PknH, PknJ, PknK, and PknL were also studied; their three-dimensional structural models were developed by using homology modeling. The main characteristics of MTPK ATP-binding sites (the non-crystallized and crystallized MTPKs, including PknE and PknI) were accounted; schemes of the main polar and nonpolar groups inside their ATP-binding sites were constructed, which are suitable for a major understanding of these proteins as antituberculotic targets. These schemes could be used for establishing comparisons between MTPKs and human PKs in order to increase selectivity of MTPK inhibitors. As a key tool for guiding medicinal chemists interested in the design of novel MTPK inhibitors, our work provides a map of the structural elements relevant for the design of more selective ATP-competitive MTPK inhibitors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Hallows KR, Alzamora R, Li H et al (2009) AMP-activated protein kinase inhibits alkaline pH- and PKA-induced apical vacuolar H+-ATPase accumulation in epididymal clear cells. Am J Physiol Cell Physiol 296:C672–C681. https://doi.org/10.1152/ajpcell.00004.2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Nesher R, Anteby E, Yedovizky M et al (2002) Beta-cell protein kinases and the dynamics of the insulin response to glucose. Diabetes 51(Suppl 1):S68–S73

    Article  CAS  PubMed  Google Scholar 

  3. Salminen A, Kaarniranta K, Haapasalo A et al (2011) AMP-activated protein kinase: a potential player in Alzheimer’s disease. J Neurochem 118:460–474. https://doi.org/10.1111/j.1471-4159.2011.07331.x

    Article  CAS  PubMed  Google Scholar 

  4. Kotlyarov A, Neininger A, Schubert C et al (1999) MAPKAP kinase 2 is essential for LPS-induced TNF-alpha biosynthesis. Nat Cell Biol 1:94–97. https://doi.org/10.1038/10061

    Article  CAS  PubMed  Google Scholar 

  5. Av-Gay Y, Davies J (1997) Components of eukaryotic-like protein signaling pathways in Mycobacterium tuberculosis. Microb Comp Genomics 2:63–73. https://doi.org/10.1089/omi.1.1997.2.63

    Article  CAS  Google Scholar 

  6. Cole ST, Brosch R, Parkhill J et al (1998) Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393:537–544. https://doi.org/10.1038/31159

    Article  CAS  PubMed  Google Scholar 

  7. Prisic S, Husson RN (2014) Mycobacterium tuberculosis serine/threonine protein kinases. Microbiol Spectr. https://doi.org/10.1128/microbiolspec.MGM2-0006-2013

    Article  PubMed  PubMed Central  Google Scholar 

  8. Chow K, Ng D, Stokes R, Johnson P (1994) Protein tyrosine phosphorylation in Mycobacterium tuberculosis. FEMS Microbiol Lett 124:203–207

    Article  CAS  PubMed  Google Scholar 

  9. Av-Gay Y, Everett M (2000) The eukaryotic-like Ser/Thr protein kinases of Mycobacterium tuberculosis. Trends Microbiol 8:238–244

    Article  CAS  PubMed  Google Scholar 

  10. Zuccotto F, Ardini E, Casale E, Angiolini M (2010) Through the “Gatekeeper Door”: exploiting the active kinase conformation. J Med Chem 53:2681–2694. https://doi.org/10.1021/jm901443h

    Article  CAS  PubMed  Google Scholar 

  11. Chakraborti PK, Matange N, Nandicoori VK et al (2011) Signalling mechanisms in Mycobacteria. Tuberc Edinb Scotl 91:432–440. https://doi.org/10.1016/j.tube.2011.04.005

    Article  CAS  Google Scholar 

  12. Khan S, Nagarajan SN, Parikh A et al (2010) Phosphorylation of enoyl-acyl carrier protein reductase InhA impacts mycobacterial growth and survival. J Biol Chem 285:37860–37871. https://doi.org/10.1074/jbc.M110.143131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Greenstein AE, MacGurn JA, Baer CE et al (2007) M. tuberculosis Ser/Thr protein kinase D phosphorylates an anti-anti-sigma factor homolog. PLoS Pathog 3:e49. https://doi.org/10.1371/journal.ppat.0030049

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Pérez J, Garcia R, Bach H et al (2006) Mycobacterium tuberculosis transporter MmpL7 is a potential substrate for kinase PknD. Biochem Biophys Res Commun 348:6–12. https://doi.org/10.1016/j.bbrc.2006.06.164

    Article  CAS  PubMed  Google Scholar 

  15. Jayakumar D, Jacobs WR, Narayanan S (2008) Protein kinase E of Mycobacterium tuberculosis has a role in the nitric oxide stress response and apoptosis in a human macrophage model of infection. Cell Microbiol 10:365–374. https://doi.org/10.1111/j.1462-5822.2007.01049.x

    Article  CAS  PubMed  Google Scholar 

  16. Molle V, Soulat D, Jault J-M et al (2004) Two FHA domains on an ABC transporter, Rv1747, mediate its phosphorylation by PknF, a Ser/Thr protein kinase from Mycobacterium tuberculosis. FEMS Microbiol Lett 234:215–223. https://doi.org/10.1016/j.femsle.2004.03.033

    Article  CAS  PubMed  Google Scholar 

  17. Deol P, Vohra R, Saini AK et al (2005) Role of Mycobacterium tuberculosis Ser/Thr kinase PknF: implications in glucose transport and cell division. J Bacteriol 187:3415–3420. https://doi.org/10.1128/JB.187.10.3415-3420.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Walburger A, Koul A, Ferrari G et al (2004) Protein kinase G from pathogenic mycobacteria promotes survival within macrophages. Science 304:1800–1804. https://doi.org/10.1126/science.1099384

    Article  CAS  PubMed  Google Scholar 

  19. O’Hare HM, Durán R, Cerveñansky C et al (2008) Regulation of glutamate metabolism by protein kinases in mycobacteria. Mol Microbiol 70:1408–1423. https://doi.org/10.1111/j.1365-2958.2008.06489.x

    Article  CAS  PubMed  Google Scholar 

  20. Rieck B, Degiacomi G, Zimmermann M et al (2017) PknG senses amino acid availability to control metabolism and virulence of Mycobacterium tuberculosis. PLoS Pathog 13:e1006399. https://doi.org/10.1371/journal.ppat.1006399

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Gómez-Velasco A, Bach H, Rana AK et al (2013) Disruption of the serine/threonine protein kinase H affects phthiocerol dimycocerosates synthesis in Mycobacterium tuberculosis. Microbiol Read Engl 159:726–736. https://doi.org/10.1099/mic.0.062067-0

    Article  CAS  Google Scholar 

  22. Sharma K, Chandra H, Gupta PK et al (2004) PknH, a transmembrane Hank’s type serine/threonine kinase from Mycobacterium tuberculosis is differentially expressed under stress conditions. FEMS Microbiol Lett 233:107–113. https://doi.org/10.1016/j.femsle.2004.01.045

    Article  CAS  PubMed  Google Scholar 

  23. Gopalaswamy R, Narayanan S, Chen B et al (2009) The serine/threonine protein kinase PknI controls the growth of Mycobacterium tuberculosis upon infection. FEMS Microbiol Lett 295:23–29. https://doi.org/10.1111/j.1574-6968.2009.01570.x

    Article  CAS  PubMed  Google Scholar 

  24. Venkatesan A, Palaniyandi K, Sharma D et al (2016) Functional characterization of PknI-Rv2159c interaction in redox homeostasis of Mycobacterium tuberculosis. Front Microbiol 7:1654. https://doi.org/10.3389/fmicb.2016.01654

    Article  PubMed  PubMed Central  Google Scholar 

  25. Singh DK, Singh PK, Tiwari S et al (2014) Phosphorylation of pyruvate kinase A by protein kinase J leads to the altered growth and differential rate of intracellular survival of mycobacteria. Appl Microbiol Biotechnol 98:10065–10076. https://doi.org/10.1007/s00253-014-5859-4

    Article  CAS  PubMed  Google Scholar 

  26. Kumar P, Kumar D, Parikh A et al (2009) The Mycobacterium tuberculosis protein kinase K modulates activation of transcription from the promoter of mycobacterial monooxygenase operon through phosphorylation of the transcriptional regulator VirS. J Biol Chem 284:11090–11099. https://doi.org/10.1074/jbc.M808705200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Canova MJ, Veyron-Churlet R, Zanella-Cleon I et al (2008) The Mycobacterium tuberculosis serine/threonine kinase PknL phosphorylates Rv2175c: mass spectrometric profiling of the activation loop phosphorylation sites and their role in the recruitment of Rv2175c. Proteomics 8:521–533. https://doi.org/10.1002/pmic.200700442

    Article  CAS  PubMed  Google Scholar 

  28. Sipos A, Pató J, Székely R et al (2015) Lead selection and characterization of antitubercular compounds using the nested chemical library. Tuberc Edinb Scotl 95(Suppl 1):S200–S206. https://doi.org/10.1016/j.tube.2015.02.028

    Article  CAS  Google Scholar 

  29. Székely R, Wáczek F, Szabadkai I et al (2008) A novel drug discovery concept for tuberculosis: inhibition of bacterial and host cell signalling. Immunol Lett 116:225–231. https://doi.org/10.1016/j.imlet.2007.12.005

    Article  CAS  PubMed  Google Scholar 

  30. Lougheed KEA, Osborne SA, Saxty B et al (2011) Effective inhibitors of the essential kinase PknB and their potential as anti-mycobacterial agents. Tuberc Edinb Scotl 91:277–286. https://doi.org/10.1016/j.tube.2011.03.005

    Article  CAS  Google Scholar 

  31. Chapman TM, Bouloc N, Buxton RS et al (2012) Substituted aminopyrimidine protein kinase B (PknB) inhibitors show activity against Mycobacterium tuberculosis. Bioorg Med Chem Lett 22:3349–3353. https://doi.org/10.1016/j.bmcl.2012.02.107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Pató J, Kéri G, Örfi L et al (2009) Novel therapeutic targets for the treatment of mycobacterial infections and compounds useful therefor. U.S. Patent US20090298842

  33. Wang T, Bemis G, Hanzelka B et al (2017) Mtb PKNA/PKNB dual inhibition provides selectivity advantages for inhibitor design to minimize host kinase interactions. ACS Med Chem Lett 8:1224–1229. https://doi.org/10.1021/acsmedchemlett.7b00239

    Article  CAS  PubMed  Google Scholar 

  34. Lee Y-V, Choi SB, Wahab HA, Choong YS (2017) Active site flexibility of Mycobacterium tuberculosis isocitrate lyase in dimer form. J Chem Inf Model 57:2351–2357. https://doi.org/10.1021/acs.jcim.7b00265

    Article  CAS  PubMed  Google Scholar 

  35. Perryman AL, Yu W, Wang X et al (2015) A virtual screen discovers novel, fragment-sized inhibitors of Mycobacterium tuberculosis InhA. J Chem Inf Model 55:645–659. https://doi.org/10.1021/ci500672v

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Espinoza-Moraga M, Njuguna NM, Mugumbate G et al (2013) In silico comparison of antimycobacterial natural products with known antituberculosis drugs. J Chem Inf Model 53:649–660. https://doi.org/10.1021/ci300467b

    Article  CAS  PubMed  Google Scholar 

  37. Silva JRA, Roitberg AE, Alves CN (2014) Catalytic mechanism of L,D-transpeptidase 2 from Mycobacterium tuberculosis described by a computational approach: insights for the design of new antibiotics drugs. J Chem Inf Model 54:2402–2410. https://doi.org/10.1021/ci5003069

    Article  CAS  PubMed  Google Scholar 

  38. Riadi G, Caballero J (2014) Easy Identification of residues involved on structural differences between nonphosphorylated and phosphorylated CDK2Cyclin A complexes using two-dimensional networks. Mol Inform 33:151–162. https://doi.org/10.1002/minf.201300100

    Article  CAS  PubMed  Google Scholar 

  39. Khuntawee W, Rungrotmongkol T, Hannongbua S (2012) Molecular dynamic behavior and binding affinity of flavonoid analogues to the cyclin dependent kinase 6/cyclin D complex. J Chem Inf Model 52:76–83. https://doi.org/10.1021/ci200304v

    Article  CAS  PubMed  Google Scholar 

  40. Mena-Ulecia K, Vergara-Jaque A, Poblete H et al (2014) Study of the affinity between the protein kinase PKA and peptide substrates derived from kemptide using molecular dynamics simulations and MM/GBSA. PLoS ONE 9:e109639. https://doi.org/10.1371/journal.pone.0109639

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Mena-Ulecia K, Gonzalez-Norambuena F, Vergara-Jaque A et al (2018) Study of the affinity between the protein kinase PKA and homoarginine-containing peptides derived from kemptide: free energy perturbation (FEP) calculations. J Comput Chem. https://doi.org/10.1002/jcc.25176

    Article  PubMed  Google Scholar 

  42. Alzate-Morales J, Caballero J (2010) Computational study of the interactions between guanine derivatives and cyclin-dependent kinase 2 (CDK2) by CoMFA and QM/MM. J Chem Inf Model 50:110–122. https://doi.org/10.1021/ci900302z

    Article  CAS  PubMed  Google Scholar 

  43. Alzate-Morales JH, Vergara-Jaque A, Caballero J (2010) Computational study on the interaction of N1 substituted pyrazole derivatives with B-Raf kinase: an unusual water wire hydrogen-bond network and novel interactions at the entrance of the active site. J Chem Inf Model 50:1101–1112. https://doi.org/10.1021/ci100049h

    Article  CAS  PubMed  Google Scholar 

  44. Caballero J, Zilocchi S, Tiznado W et al (2011) Binding studies and quantitative structure-activity relationship of 3-amino-1H-indazoles as inhibitors of GSK3β. Chem Biol Drug Des 78:631–641. https://doi.org/10.1111/j.1747-0285.2011.01186.x

    Article  CAS  PubMed  Google Scholar 

  45. Caballero J, Alzate-Morales JH, Vergara-Jaque A (2011) Investigation of the differences in activity between hydroxycycloalkyl N1 substituted pyrazole derivatives as inhibitors of B-Raf kinase by using docking, molecular dynamics, QM/MM, and fragment-based de novo design: study of binding mode of diastereomer compounds. J Chem Inf Model 51:2920–2931. https://doi.org/10.1021/ci200306w

    Article  CAS  PubMed  Google Scholar 

  46. Caballero J, Alzate-Morales JH (2012) Molecular dynamics of protein kinase-inhibitor complexes: a valid structural information. Curr Pharm Des 18:2946–2963

    Article  CAS  PubMed  Google Scholar 

  47. Caballero J, Muñoz C, Alzate-Morales JH et al (2012) Synthesis, in silico, in vitro, and in vivo investigation of 5-[11C]methoxy-substituted sunitinib, a tyrosine kinase inhibitor of VEGFR-2. Eur J Med Chem 58:272–280. https://doi.org/10.1016/j.ejmech.2012.10.020

    Article  CAS  PubMed  Google Scholar 

  48. Munoz C, Adasme F, Alzate-Morales JH et al (2012) Study of differences in the VEGFR2 inhibitory activities between semaxanib and SU5205 using 3D-QSAR, docking, and molecular dynamics simulations. J Mol Graph Model 32:39–48. https://doi.org/10.1016/j.jmgm.2011.10.005

    Article  CAS  PubMed  Google Scholar 

  49. Quesada-Romero L, Caballero J (2014) Docking and quantitative structure–activity relationship of oxadiazole derivates as inhibitors of GSK3beta. Mol Divers 18:149–159. https://doi.org/10.1007/s11030-013-9483-5

    Article  CAS  PubMed  Google Scholar 

  50. Quesada-Romero L, Mena-Ulecia K, Tiznado W, Caballero J (2014) Insights into the interactions between maleimide derivates and GSK3β combining molecular docking and QSAR. PLoS ONE 9:e102212. https://doi.org/10.1371/journal.pone.0102212

    Article  PubMed  PubMed Central  Google Scholar 

  51. Adasme-Carreño F, Muñoz-Gutierrez C, Caballero J, Alzate-Morales J (2014) Performance of the MM/GBSA scoring using a binding site hydrogen bond network-based frame selection: the protein kinase case. Phys Chem Chem Phys 16:14047–14058. https://doi.org/10.1039/C4CP01378F

    Article  PubMed  Google Scholar 

  52. Navarro-Retamal C, Caballero J (2016) Flavonoids as CDK1 inhibitors: insights in their binding orientations and structure-activity relationship. PLoS ONE 11:e0161111. https://doi.org/10.1371/journal.pone.0161111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Navarro-Retamal C, Caballero J (2018) Molecular modeling of tau proline-directed protein kinase (PDPK) inhibitors. In: Computational modeling of drugs against Alzheimer’s disease. Humana Press, New York, pp 305–345

    Chapter  Google Scholar 

  54. Gay LM, Ng H-L, Alber T (2006) A conserved dimer and global conformational changes in the structure of apo-PknE Ser/Thr protein kinase from Mycobacterium tuberculosis. J Mol Biol 360:409–420. https://doi.org/10.1016/j.jmb.2006.05.015

    Article  CAS  PubMed  Google Scholar 

  55. Lisa M-N, Wagner T, Alexandre M et al (2017) The crystal structure of PknI from Mycobacterium tuberculosis shows an inactive, pseudokinase-like conformation. FEBS J 284:602–614. https://doi.org/10.1111/febs.14003

    Article  CAS  PubMed  Google Scholar 

  56. Yan Q, Jiang D, Qian L et al (2017) Structural insight into the activation of PknI kinase from M. tuberculosis via dimerization of the extracellular sensor domain. Structure 25:1286–1294.e4. https://doi.org/10.1016/j.str.2017.06.010

    Article  CAS  PubMed  Google Scholar 

  57. Ravala SK, Singh S, Yadav GS et al (2015) Evidence that phosphorylation of threonine in the GT motif triggers activation of PknA, a eukaryotic-type serine/threonine kinase from Mycobacterium tuberculosis. FEBS J 282:1419–1431. https://doi.org/10.1111/febs.13230

    Article  CAS  PubMed  Google Scholar 

  58. Mieczkowski C, Iavarone AT, Alber T (2008) Auto-activation mechanism of the Mycobacterium tuberculosis PknB receptor Ser/Thr kinase. EMBO J 27:3186–3197. https://doi.org/10.1038/emboj.2008.236

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Young TA, Delagoutte B, Endrizzi JA et al (2003) Structure of Mycobacterium tuberculosis PknB supports a universal activation mechanism for Ser/Thr protein kinases. Nat Struct Biol 10:168–174. https://doi.org/10.1038/nsb897

    Article  CAS  PubMed  Google Scholar 

  60. Wehenkel A, Fernandez P, Bellinzoni M et al (2006) The structure of PknB in complex with mitoxantrone, an ATP-competitive inhibitor, suggests a mode of protein kinase regulation in mycobacteria. FEBS Lett 580:3018–3022. https://doi.org/10.1016/j.febslet.2006.04.046

    Article  CAS  PubMed  Google Scholar 

  61. Scherr N, Honnappa S, Kunz G et al (2007) Structural basis for the specific inhibition of protein kinase G, a virulence factor of Mycobacterium tuberculosis. Proc Natl Acad Sci USA 104:12151–12156. https://doi.org/10.1073/pnas.0702842104

    Article  CAS  PubMed  Google Scholar 

  62. Maestro (2014) version 9.7, Schrödinger. LLC, New York

    Google Scholar 

  63. Olsson MHM, Søndergaard CR, Rostkowski M, Jensen JH (2011) PROPKA3: consistent treatment of internal and surface residues in empirical pKa predictions. J Chem Theory Comput 7:525–537. https://doi.org/10.1021/ct100578z

    Article  CAS  Google Scholar 

  64. Madhavi Sastry G, Adzhigirey M, Day T et al (2013) Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments. J Comput Aided Mol Des 27:221–234. https://doi.org/10.1007/s10822-013-9644-8

    Article  CAS  Google Scholar 

  65. LigPrep (2014) version 2.9, Schrödinger. LLC, New York

    Google Scholar 

  66. Epik (2014) version 2.7, Schrödinger. LLC, New York

    Google Scholar 

  67. Friesner RA, Banks JL, Murphy RB et al (2004) Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem 47:1739–1749. https://doi.org/10.1021/jm0306430

    Article  CAS  Google Scholar 

  68. Friesner RA, Murphy RB, Repasky MP et al (2006) Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein—ligand complexes. J Med Chem 49:6177–6196. https://doi.org/10.1021/jm051256o

    Article  CAS  Google Scholar 

  69. Muñoz-Gutierrez C, Adasme-Carreño F, Fuentes E et al (2016) Computational study of the binding orientation and affinity of PPARγ agonists: inclusion of ligand-induced fit by cross-docking. RSC Adv 6:64756–64768. https://doi.org/10.1039/C6RA12084A

    Article  CAS  Google Scholar 

  70. Ramírez D, Caballero J (2018) Is it reliable to take the molecular docking top scoring position as the best solution without considering available. structural data? Molecules 23:1038. https://doi.org/10.3390/molecules23051038

    Article  CAS  PubMed Central  Google Scholar 

  71. Bateman A, Martin MJ, O’Donovan C et al (2017) UniProt: the universal protein knowledgebase. Nucleic Acids Res 45:D158–D169. https://doi.org/10.1093/nar/gkw1099

    Article  CAS  Google Scholar 

  72. Bordoli L, Kiefer F, Arnold K et al (2009) Protein structure homology modeling using SWISS-MODEL workspace. Nat Protoc 4:1–13. https://doi.org/10.1038/nprot.2008.197

    Article  CAS  PubMed  Google Scholar 

  73. Van Der Spoel D, Lindahl E, Hess B et al (2005) GROMACS: fast, flexible, and free. J Comput Chem 26:1701–1718. https://doi.org/10.1002/jcc.20291

    Article  CAS  Google Scholar 

  74. Abraham MJ, Murtola T, Schulz R et al (2015) GROMACS: high performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX 1–2:19–25. https://doi.org/10.1016/j.softx.2015.06.001

    Article  Google Scholar 

  75. Hess B, Bekker H, Berendsen HJC, Fraaije JGEM (1997) LINCS: a linear constraint solver for molecular simulations. J Comput Chem 18:1463–1472

    Article  CAS  Google Scholar 

  76. Laskowski RA, MacArthur MW, Moss DS, Thornton JM (1993) PROCHECK: a program to check the stereochemical quality of protein structures. J Appl Crystallogr 26:283–291. https://doi.org/10.1107/S0021889892009944

    Article  CAS  Google Scholar 

  77. Vriend G (1990) WHAT IF: a molecular modeling and drug design program. J Mol Graph 8:52–56, 29

    Article  CAS  PubMed  Google Scholar 

  78. Hooft RW, Vriend G, Sander C, Abola EE (1996) Errors in protein structures. Nature 381:272. https://doi.org/10.1038/381272a0

    Article  CAS  PubMed  Google Scholar 

  79. MacArthur MW, Laskowski RA, Thornton JM (1994) Knowledge-based validation of protein structure coordinates derived by X-ray crystallography and NMR spectroscopy. Curr Opin Struct Biol 4:731–737. https://doi.org/10.1016/S0959-440X(94)90172-4

    Article  CAS  Google Scholar 

  80. Bowie JU, Lüthy R, Eisenberg D (1991) A method to identify protein sequences that fold into a known three-dimensional structure. Science 253:164–170

    Article  CAS  Google Scholar 

  81. Pontius J, Richelle J, Wodak SJ (1996) Deviations from standard atomic volumes as a quality measure for protein crystal structures. J Mol Biol 264:121–136. https://doi.org/10.1006/jmbi.1996.0628

    Article  CAS  PubMed  Google Scholar 

  82. Wiederstein M, Sippl MJ (2007) ProSA-web: interactive web service for the recognition of errors in three-dimensional structures of proteins. Nucleic Acids Res 35:W407–W410. https://doi.org/10.1093/nar/gkm290

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Thanks to the funds of FONDECYT postdoctoral project N0 3150035 (AMB and JC). JC also acknowledges funds of FONDECYT Regular N0 1170718. CNR also acknowledges funds of FONDECYT postdoctoral project N0 3170434.

Author information

Authors and Affiliations

  1. Centro de Bioinformática y Simulación Molecular (CBSM), Universidad de Talca, 1 Poniente No. 1141, Casilla 721, Talca, Chile

    Julio Caballero, Alejandro Morales-Bayuelo & Carlos Navarro-Retamal

Authors
  1. Julio Caballero
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alejandro Morales-Bayuelo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Carlos Navarro-Retamal
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Julio Caballero.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (ZIP 1329 KB)

Supplementary material 2 (DOCX 10296 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Caballero, J., Morales-Bayuelo, A. & Navarro-Retamal, C. Mycobacterium tuberculosis serine/threonine protein kinases: structural information for the design of their specific ATP-competitive inhibitors. J Comput Aided Mol Des 32, 1315–1336 (2018). https://doi.org/10.1007/s10822-018-0173-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10822-018-0173-3

Keywords

Search

Navigation