Serine/threonine-protein kinase PknB

Details

Name
Serine/threonine-protein kinase PknB
Synonyms
  • 2.7.11.1
Gene Name
pknB
Organism
Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
Amino acid sequence
>lcl|BSEQ0051163|Serine/threonine-protein kinase PknB
MTTPSHLSDRYELGEILGFGGMSEVHLARDLRLHRDVAVKVLRADLARDPSFYLRFRREA
QNAAALNHPAIVAVYDTGEAETPAGPLPYIVMEYVDGVTLRDIVHTEGPMTPKRAIEVIA
DACQALNFSHQNGIIHRDVKPANIMISATNAVKVMDFGIARAIADSGNSVTQTAAVIGTA
QYLSPEQARGDSVDARSDVYSLGCVLYEVLTGEPPFTGDSPVSVAYQHVREDPIPPSARH
EGLSADLDAVVLKALAKNPENRYQTAAEMRADLVRVHNGEPPEAPKVLTDAERTSLLSSA
AGNLSGPRTDPLPRQDLDDTDRDRSIGSVGRWVAVVAVLAVLTVVVTIAINTFGGITRDV
QVPDVRGQSSADAIATLQNRGFKIRTLQKPDSTIPPDHVIGTDPAANTSVSAGDEITVNV
STGPEQREIPDVSTLTYAEAVKKLTAAGFGRFKQANSPSTPELVGKVIGTNPPANQTSAI
TNVVIIIVGSGPATKDIPDVAGQTVDVAQKNLNVYGFTKFSQASVDSPRPAGEVTGTNPP
AGTTVPVDSVIELQVSKGNQFVMPDLSGMFWVDAEPRLRALGWTGMLDKGADVDAGGSQH
NRVVYQNPPAGTGVNRDGIITLRFGQ
Number of residues
626
Molecular Weight
66509.265
Theoretical pI
Not Available
GO Classification
Functions
ATP binding / identical protein binding / manganese ion binding / protein kinase activity / protein serine/threonine kinase activity
Processes
growth / negative regulation of catalytic activity / negative regulation of fatty acid biosynthetic process / negative regulation of protein binding / pathogenesis / positive regulation of catalytic activity / positive regulation of DNA binding / protein autophosphorylation / regulation of cell shape / regulation of transferase activity / response to host immune response
Components
cell wall / integral component of membrane / plasma membrane
General Function
Protein kinase that regulates many aspects of mycobacterial physiology, and is critical for growth in vitro and survival of the pathogen in the host (PubMed:24706757). Is a key component of a signal transduction pathway that regulates cell growth, cell shape and cell division via phosphorylation of target proteins such as GarA, GlmU, PapA5, PbpA, FhaB (Rv0019c), FhaA (Rv0020c), MviN, PstP, EmbR, Rv1422, Rv1747 and RseA (PubMed:15978616, PubMed:15985609, PubMed:15987910, PubMed:16436437, PubMed:16817899, PubMed:16980473, PubMed:19121323, PubMed:19826007, PubMed:20025669, PubMed:21423706, PubMed:22275220). Also catalyzes the phosphorylation of the core proteasome alpha-subunit (PrcA), and thereby regulates the proteolytic activity of the proteasome (PubMed:25224505). Is a major regulator of the oxygen-dependent replication switch since PknB activity is necessary for reactivation of cells from the hypoxic state (PubMed:24409094). Shows a strong preference for Thr versus Ser as the phosphoacceptor. Overexpression of PknB alters cell morphology and leads to cell death (PubMed:24706757) (PubMed:24409094).
Specific Function
Atp binding
Pfam Domain Function
Transmembrane Regions
333-353
Cellular Location
Cell membrane
Gene sequence
>lcl|BSEQ0051164|Serine/threonine-protein kinase PknB (pknB)
ATGACCACCCCTTCCCACCTGTCCGACCGCTACGAACTTGGCGAAATCCTTGGATTTGGG
GGCATGTCCGAGGTCCACCTGGCCCGCGACCTCCGGTTGCACCGCGACGTTGCGGTCAAG
GTGCTGCGCGCTGATCTAGCCCGCGATCCCAGTTTTTACCTTCGCTTCCGGCGTGAGGCG
CAAAACGCCGCGGCATTGAACCACCCTGCAATCGTCGCGGTCTACGACACCGGTGAAGCC
GAAACGCCCGCCGGGCCATTGCCCTACATCGTCATGGAATACGTCGACGGCGTTACCCTG
CGCGACATTGTCCACACCGAAGGGCCGATGACGCCCAAACGCGCCATCGAGGTCATCGCC
GACGCCTGCCAAGCGCTGAACTTCAGTCATCAGAACGGAATCATCCACCGTGACGTCAAG
CCGGCGAACATCATGATCAGCGCGACCAATGCAGTAAAGGTGATGGATTTCGGCATCGCC
CGCGCCATTGCCGACAGCGGCAACAGCGTGACCCAGACCGCAGCAGTGATCGGCACGGCG
CAGTACCTGTCACCCGAACAGGCCCGGGGTGATTCCGTCGACGCCCGATCCGATGTCTAT
TCCTTGGGCTGTGTTCTTTATGAAGTCCTCACCGGGGAGCCACCTTTCACCGGCGACTCA
CCCGTCTCGGTTGCCTACCAACATGTGCGCGAAGACCCGATCCCACCTTCGGCGCGGCAC
GAAGGCCTCTCCGCCGACCTGGACGCCGTCGTTCTCAAGGCGCTGGCCAAAAATCCGGAA
AACCGCTATCAGACAGCGGCGGAGATGCGCGCCGACCTGGTCCGCGTGCACAACGGTGAG
CCGCCCGAGGCGCCCAAAGTGCTCACCGATGCCGAGCGGACCTCGCTGCTGTCGTCTGCG
GCCGGCAACCTTAGCGGTCCGCGCACCGATCCGCTACCACGCCAGGACTTAGACGACACC
GACCGTGACCGCAGCATCGGTTCGGTGGGCCGTTGGGTTGCGGTGGTCGCCGTGCTCGCT
GTGCTGACCGTCGTGGTAACCATCGCCATCAACACGTTCGGCGGCATCACCCGCGACGTT
CAAGTTCCCGACGTTCGGGGTCAATCCTCCGCCGACGCCATCGCCACACTGCAAAACCGG
GGCTTCAAAATCCGCACCTTGCAGAAGCCGGACTCGACAATCCCACCGGACCACGTTATC
GGCACCGACCCGGCCGCCAACACGTCGGTGAGTGCAGGCGACGAGATCACAGTCAACGTG
TCCACCGGACCCGAGCAACGCGAAATACCCGACGTCTCCACGCTGACATACGCCGAAGCG
GTCAAGAAACTGACTGCCGCCGGATTCGGCCGCTTCAAGCAAGCGAATTCGCCGTCCACC
CCGGAACTGGTGGGCAAGGTCATCGGGACCAACCCGCCAGCCAACCAGACGTCGGCCATC
ACCAATGTGGTCATCATCATCGTTGGCTCTGGTCCGGCGACCAAAGACATTCCCGATGTC
GCGGGCCAGACCGTCGACGTGGCGCAGAAGAACCTCAACGTCTACGGCTTCACCAAATTC
AGTCAGGCCTCGGTGGACAGCCCCCGTCCCGCCGGCGAGGTGACCGGCACCAATCCACCC
GCAGGCACCACAGTTCCGGTCGATTCAGTCATCGAACTACAGGTGTCCAAGGGCAACCAA
TTCGTCATGCCCGACCTATCCGGCATGTTCTGGGTCGACGCCGAACCACGATTGCGCGCG
CTGGGCTGGACCGGGATGCTCGACAAAGGGGCCGACGTCGACGCCGGTGGCTCCCAACAC
AACCGGGTCGTCTATCAAAACCCGCCGGCGGGGACCGGCGTCAACCGGGACGGCATCATC
ACGCTGAGGTTCGGCCAGTAG
Chromosome Location
Not Available
Locus
Not Available
External Identifiers
ResourceLink
UniProtKB IDP9WI81
UniProtKB Entry NamePKNB_MYCTU
General References
  1. Cole ST, Brosch R, Parkhill J, Garnier T, Churcher C, Harris D, Gordon SV, Eiglmeier K, Gas S, Barry CE 3rd, Tekaia F, Badcock K, Basham D, Brown D, Chillingworth T, Connor R, Davies R, Devlin K, Feltwell T, Gentles S, Hamlin N, Holroyd S, Hornsby T, Jagels K, Krogh A, McLean J, Moule S, Murphy L, Oliver K, Osborne J, Quail MA, Rajandream MA, Rogers J, Rutter S, Seeger K, Skelton J, Squares R, Squares S, Sulston JE, Taylor K, Whitehead S, Barrell BG: Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature. 1998 Jun 11;393(6685):537-44. [Article]
  2. Boitel B, Ortiz-Lombardia M, Duran R, Pompeo F, Cole ST, Cervenansky C, Alzari PM: PknB kinase activity is regulated by phosphorylation in two Thr residues and dephosphorylation by PstP, the cognate phospho-Ser/Thr phosphatase, in Mycobacterium tuberculosis. Mol Microbiol. 2003 Sep;49(6):1493-508. [Article]
  3. Av-Gay Y, Jamil S, Drews SJ: Expression and characterization of the Mycobacterium tuberculosis serine/threonine protein kinase PknB. Infect Immun. 1999 Nov;67(11):5676-82. [Article]
  4. Duran R, Villarino A, Bellinzoni M, Wehenkel A, Fernandez P, Boitel B, Cole ST, Alzari PM, Cervenansky C: Conserved autophosphorylation pattern in activation loops and juxtamembrane regions of Mycobacterium tuberculosis Ser/Thr protein kinases. Biochem Biophys Res Commun. 2005 Aug 5;333(3):858-67. [Article]
  5. Kang CM, Abbott DW, Park ST, Dascher CC, Cantley LC, Husson RN: The Mycobacterium tuberculosis serine/threonine kinases PknA and PknB: substrate identification and regulation of cell shape. Genes Dev. 2005 Jul 15;19(14):1692-704. Epub 2005 Jun 28. [Article]
  6. Villarino A, Duran R, Wehenkel A, Fernandez P, England P, Brodin P, Cole ST, Zimny-Arndt U, Jungblut PR, Cervenansky C, Alzari PM: Proteomic identification of M. tuberculosis protein kinase substrates: PknB recruits GarA, a FHA domain-containing protein, through activation loop-mediated interactions. J Mol Biol. 2005 Jul 29;350(5):953-63. [Article]
  7. Grundner C, Gay LM, Alber T: Mycobacterium tuberculosis serine/threonine kinases PknB, PknD, PknE, and PknF phosphorylate multiple FHA domains. Protein Sci. 2005 Jul;14(7):1918-21. [Article]
  8. Sharma K, Gupta M, Krupa A, Srinivasan N, Singh Y: EmbR, a regulatory protein with ATPase activity, is a substrate of multiple serine/threonine kinases and phosphatase in Mycobacterium tuberculosis. FEBS J. 2006 Jun;273(12):2711-21. [Article]
  9. Fernandez P, Saint-Joanis B, Barilone N, Jackson M, Gicquel B, Cole ST, Alzari PM: The Ser/Thr protein kinase PknB is essential for sustaining mycobacterial growth. J Bacteriol. 2006 Nov;188(22):7778-84. Epub 2006 Sep 15. [Article]
  10. Dasgupta A, Datta P, Kundu M, Basu J: The serine/threonine kinase PknB of Mycobacterium tuberculosis phosphorylates PBPA, a penicillin-binding protein required for cell division. Microbiology. 2006 Feb;152(Pt 2):493-504. [Article]
  11. Gupta M, Sajid A, Arora G, Tandon V, Singh Y: Forkhead-associated domain-containing protein Rv0019c and polyketide-associated protein PapA5, from substrates of serine/threonine protein kinase PknB to interacting proteins of Mycobacterium tuberculosis. J Biol Chem. 2009 Dec 11;284(50):34723-34. doi: 10.1074/jbc.M109.058834. Epub 2009 Oct 13. [Article]
  12. Parikh A, Verma SK, Khan S, Prakash B, Nandicoori VK: PknB-mediated phosphorylation of a novel substrate, N-acetylglucosamine-1-phosphate uridyltransferase, modulates its acetyltransferase activity. J Mol Biol. 2009 Feb 20;386(2):451-64. doi: 10.1016/j.jmb.2008.12.031. Epub 2008 Dec 24. [Article]
  13. Barik S, Sureka K, Mukherjee P, Basu J, Kundu M: RseA, the SigE specific anti-sigma factor of Mycobacterium tuberculosis, is inactivated by phosphorylation-dependent ClpC1P2 proteolysis. Mol Microbiol. 2010 Feb;75(3):592-606. doi: 10.1111/j.1365-2958.2009.07008.x. Epub 2009 Dec 16. [Article]
  14. Lombana TN, Echols N, Good MC, Thomsen ND, Ng HL, Greenstein AE, Falick AM, King DS, Alber T: Allosteric activation mechanism of the Mycobacterium tuberculosis receptor Ser/Thr protein kinase, PknB. Structure. 2010 Dec 8;18(12):1667-77. doi: 10.1016/j.str.2010.09.019. [Article]
  15. Kelkar DS, Kumar D, Kumar P, Balakrishnan L, Muthusamy B, Yadav AK, Shrivastava P, Marimuthu A, Anand S, Sundaram H, Kingsbury R, Harsha HC, Nair B, Prasad TS, Chauhan DS, Katoch K, Katoch VM, Kumar P, Chaerkady R, Ramachandran S, Dash D, Pandey A: Proteogenomic analysis of Mycobacterium tuberculosis by high resolution mass spectrometry. Mol Cell Proteomics. 2011 Dec;10(12):M111.011627. doi: 10.1074/mcp.M111.011445. Epub 2011 Oct 3. [Article]
  16. Sajid A, Arora G, Gupta M, Upadhyay S, Nandicoori VK, Singh Y: Phosphorylation of Mycobacterium tuberculosis Ser/Thr phosphatase by PknA and PknB. PLoS One. 2011 Mar 9;6(3):e17871. doi: 10.1371/journal.pone.0017871. [Article]
  17. Mir M, Asong J, Li X, Cardot J, Boons GJ, Husson RN: The extracytoplasmic domain of the Mycobacterium tuberculosis Ser/Thr kinase PknB binds specific muropeptides and is required for PknB localization. PLoS Pathog. 2011 Jul;7(7):e1002182. doi: 10.1371/journal.ppat.1002182. Epub 2011 Jul 28. [Article]
  18. Roumestand C, Leiba J, Galophe N, Margeat E, Padilla A, Bessin Y, Barthe P, Molle V, Cohen-Gonsaud M: Structural insight into the Mycobacterium tuberculosis Rv0020c protein and its interaction with the PknB kinase. Structure. 2011 Oct 12;19(10):1525-34. doi: 10.1016/j.str.2011.07.011. [Article]
  19. Gee CL, Papavinasasundaram KG, Blair SR, Baer CE, Falick AM, King DS, Griffin JE, Venghatakrishnan H, Zukauskas A, Wei JR, Dhiman RK, Crick DC, Rubin EJ, Sassetti CM, Alber T: A phosphorylated pseudokinase complex controls cell wall synthesis in mycobacteria. Sci Signal. 2012 Jan 24;5(208):ra7. doi: 10.1126/scisignal.2002525. [Article]
  20. Chawla Y, Upadhyay S, Khan S, Nagarajan SN, Forti F, Nandicoori VK: Protein kinase B (PknB) of Mycobacterium tuberculosis is essential for growth of the pathogen in vitro as well as for survival within the host. J Biol Chem. 2014 May 16;289(20):13858-75. doi: 10.1074/jbc.M114.563536. Epub 2014 Apr 4. [Article]
  21. Anandan T, Han J, Baun H, Nyayapathy S, Brown JT, Dial RL, Moltalvo JA, Kim MS, Yang SH, Ronning DR, Husson RN, Suh J, Kang CM: Phosphorylation regulates mycobacterial proteasome. J Microbiol. 2014 Sep;52(9):743-54. doi: 10.1007/s12275-014-4416-2. Epub 2014 Sep 2. [Article]
  22. Ortega C, Liao R, Anderson LN, Rustad T, Ollodart AR, Wright AT, Sherman DR, Grundner C: Mycobacterium tuberculosis Ser/Thr protein kinase B mediates an oxygen-dependent replication switch. PLoS Biol. 2014 Jan;12(1):e1001746. doi: 10.1371/journal.pbio.1001746. Epub 2014 Jan 7. [Article]
  23. Ortiz-Lombardia M, Pompeo F, Boitel B, Alzari PM: Crystal structure of the catalytic domain of the PknB serine/threonine kinase from Mycobacterium tuberculosis. J Biol Chem. 2003 Apr 11;278(15):13094-100. Epub 2003 Jan 27. [Article]
  24. Young TA, Delagoutte B, Endrizzi JA, Falick AM, Alber T: Structure of Mycobacterium tuberculosis PknB supports a universal activation mechanism for Ser/Thr protein kinases. Nat Struct Biol. 2003 Mar;10(3):168-74. [Article]
  25. Wehenkel A, Fernandez P, Bellinzoni M, Catherinot V, Barilone N, Labesse G, Jackson M, Alzari PM: The structure of PknB in complex with mitoxantrone, an ATP-competitive inhibitor, suggests a mode of protein kinase regulation in mycobacteria. FEBS Lett. 2006 May 29;580(13):3018-22. Epub 2006 Apr 27. [Article]
  26. Mieczkowski C, Iavarone AT, Alber T: Auto-activation mechanism of the Mycobacterium tuberculosis PknB receptor Ser/Thr kinase. EMBO J. 2008 Dec 3;27(23):3186-97. doi: 10.1038/emboj.2008.236. Epub 2008 Nov 13. [Article]
  27. Barthe P, Mukamolova GV, Roumestand C, Cohen-Gonsaud M: The structure of PknB extracellular PASTA domain from mycobacterium tuberculosis suggests a ligand-dependent kinase activation. Structure. 2010 May 12;18(5):606-15. doi: 10.1016/j.str.2010.02.013. [Article]

Drug Relations

Drug Relations
DrugBank IDNameDrug groupPharmacological action?ActionsDetails
DB02930Adenosine 5'-[gamma-thio]triphosphateexperimentalunknownDetails
DB03909Adenosine-5'-[Beta, Gamma-Methylene]TriphosphateexperimentalunknownDetails
DB12010Fostamatinibapproved, investigationalunknowninhibitorDetails