6b2p: Difference between revisions

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<StructureSection load='6b2p' size='340' side='right'caption='[[6b2p]], [[Resolution|resolution]] 3.01&Aring;' scene=''>
<StructureSection load='6b2p' size='340' side='right'caption='[[6b2p]], [[Resolution|resolution]] 3.01&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[6b2p]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6B2P OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6B2P FirstGlance]. <br>
<table><tr><td colspan='2'>[[6b2p]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6B2P OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6B2P FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CJJ:5-{5-chloro-4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}thiophene-2-sulfonamide'>CJJ</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.01&#8491;</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span></td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CJJ:5-{5-chloro-4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}thiophene-2-sulfonamide'>CJJ</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6b2p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6b2p OCA], [http://pdbe.org/6b2p PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6b2p RCSB], [http://www.ebi.ac.uk/pdbsum/6b2p PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6b2p ProSAT]</span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6b2p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6b2p OCA], [https://pdbe.org/6b2p PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6b2p RCSB], [https://www.ebi.ac.uk/pdbsum/6b2p PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6b2p ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/PKNB_MYCTO PKNB_MYCTO]] Protein kinase that regulates many aspects of mycobacterial physiology. Is a key component of a signal transduction pathway that regulates cell growth, cell shape and cell division via phosphorylation of target proteins.[UniProtKB:P9WI81]
[https://www.uniprot.org/uniprot/PKNB_MYCTU PKNB_MYCTU] Key component of a signal transduction pathway that regulates cell growth 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. Shows a strong preference for Thr versus Ser as the phosphoacceptor.<ref>PMID:15985609</ref> <ref>PMID:15978616</ref> <ref>PMID:15987910</ref> <ref>PMID:16817899</ref> <ref>PMID:16980473</ref> <ref>PMID:16436437</ref> <ref>PMID:19826007</ref> <ref>PMID:19121323</ref> <ref>PMID:20025669</ref> <ref>PMID:21423706</ref> <ref>PMID:22275220</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Drug resistant tuberculosis (TB) infections are on the rise and antibiotics that inhibit Mycobacterium tuberculosis through a novel mechanism could be an important component of evolving TB therapy. Protein kinase A (PknA) and protein kinase B (PknB) are both essential serine-threonine kinases in M. tuberculosis. Given the extensive knowledge base in kinase inhibition, these enzymes present an interesting opportunity for antimycobacterial drug discovery. This study focused on targeting both PknA and PknB while improving the selectivity window over related mammalian kinases. Compounds achieved potent inhibition (Ki approximately 5 nM) of both PknA and PknB. A binding pocket unique to mycobacterial kinases was identified. Substitutions that filled this pocket resulted in a 100-fold differential against a broad selection of mammalian kinases. Reducing lipophilicity improved antimycobacterial activity with the most potent compounds achieving minimum inhibitory concentrations ranging from 3 to 5 muM (1-2 mug/mL) against the H37Ra isolate of M. tuberculosis.
 
Mtb PKNA/PKNB Dual Inhibition Provides Selectivity Advantages for Inhibitor Design To Minimize Host Kinase Interactions.,Wang T, Bemis G, Hanzelka B, Zuccola H, Wynn M, Moody CS, Green J, Locher C, Liu A, Gao H, Xu Y, Wang S, Wang J, Bennani YL, Thomson JA, Muh U ACS Med Chem Lett. 2017 Nov 28;8(12):1224-1229. doi:, 10.1021/acsmedchemlett.7b00239. eCollection 2017 Dec 14. PMID:29259738<ref>PMID:29259738</ref>
 
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6b2p" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
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</StructureSection>
</StructureSection>
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Non-specific serine/threonine protein kinase]]
[[Category: Mycobacterium tuberculosis]]
[[Category: Zuccola, H J]]
[[Category: Zuccola HJ]]
[[Category: Drug design]]
[[Category: Kinase]]
[[Category: Transferase-inhibitor complex]]
[[Category: Tuberculosis]]

Latest revision as of 17:19, 13 March 2024

Dual Inhibition of the Essential Protein Kinases A and B in Mycobacterium tuberculosisDual Inhibition of the Essential Protein Kinases A and B in Mycobacterium tuberculosis

Structural highlights

6b2p is a 1 chain structure with sequence from Mycobacterium tuberculosis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 3.01Å
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PKNB_MYCTU Key component of a signal transduction pathway that regulates cell growth 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. Shows a strong preference for Thr versus Ser as the phosphoacceptor.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11]

See Also

References

  1. ↑ 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. PMID:15985609 doi:http://dx.doi.org/10.1101/gad.1311105
  2. ↑ 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. PMID:15978616 doi:http://dx.doi.org/10.1016/j.jmb.2005.05.049
  3. ↑ 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. PMID:15987910 doi:http://dx.doi.org/10.1110/ps.051413405
  4. ↑ 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. PMID:16817899 doi:http://dx.doi.org/10.1111/j.1742-4658.2006.05289.x
  5. ↑ 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. PMID:16980473 doi:http://dx.doi.org/10.1128/JB.00963-06
  6. ↑ 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. PMID:16436437 doi:http://dx.doi.org/152/2/493
  7. ↑ 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. Epub 2009 Oct 13. PMID:19826007 doi:http://dx.doi.org/M109.058834
  8. ↑ 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. Epub 2008 Dec 24. PMID:19121323 doi:10.1016/j.jmb.2008.12.031
  9. ↑ 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. PMID:20025669 doi:http://dx.doi.org/10.1111/j.1365-2958.2009.07008.x
  10. ↑ 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. PMID:21423706 doi:http://dx.doi.org/10.1371/journal.pone.0017871
  11. ↑ 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. PMID:22275220 doi:10.1126/scisignal.2002525

6b2p, resolution 3.01Å

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