6b2p

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Current revision (14:19, 13 March 2024) (edit) (undo)
 
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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 ==
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<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>
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<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>
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</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>
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</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>
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<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>
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<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>
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<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>
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<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 ==
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[[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]
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[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>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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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.
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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>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 6b2p" style="background-color:#fffaf0;"></div>
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==See Also==
==See Also==
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</StructureSection>
</StructureSection>
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Non-specific serine/threonine protein kinase]]
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[[Category: Mycobacterium tuberculosis]]
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[[Category: Zuccola, H J]]
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[[Category: Zuccola HJ]]
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[[Category: Drug design]]
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[[Category: Kinase]]
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[[Category: Transferase-inhibitor complex]]
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[[Category: Tuberculosis]]
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Current revision

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

PDB ID 6b2p

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OCA

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