6b2q

From Proteopedia

(Difference between revisions)

Current revision

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

Structural highlights

6b2q is a 4 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 2.88Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PKNA_MYCTU Key component of a signal transduction pathway that regulates cell growth and cell division via phosphorylation of target proteins such as FtsZ, Wag31, GlmU, FhaB, PstP, EmbR and Rv1422. Shows a strong preference for Thr versus Ser as the phosphoacceptor.^[1] ^[2] ^[3] ^[4] ^[5] ^[6]

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^[7]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ 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
↑ 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
↑ 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
↑ Sureka K, Hossain T, Mukherjee P, Chatterjee P, Datta P, Kundu M, Basu J. Novel role of phosphorylation-dependent interaction between FtsZ and FipA in mycobacterial cell division. PLoS One. 2010 Jan 6;5(1):e8590. doi: 10.1371/journal.pone.0008590. PMID:20066037 doi:http://dx.doi.org/10.1371/journal.pone.0008590
↑ Jani C, Eoh H, Lee JJ, Hamasha K, Sahana MB, Han JS, Nyayapathy S, Lee JY, Suh JW, Lee SH, Rehse SJ, Crick DC, Kang CM. Regulation of polar peptidoglycan biosynthesis by Wag31 phosphorylation in mycobacteria. BMC Microbiol. 2010 Dec 29;10:327. doi: 10.1186/1471-2180-10-327. PMID:21190553 doi:http://dx.doi.org/10.1186/1471-2180-10-327
↑ 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
↑ 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. Mtb PKNA/PKNB Dual Inhibition Provides Selectivity Advantages for Inhibitor Design To Minimize Host Kinase Interactions. ACS Med Chem Lett. 2017 Nov 28;8(12):1224-1229. doi:, 10.1021/acsmedchemlett.7b00239. eCollection 2017 Dec 14. PMID:29259738 doi:http://dx.doi.org/10.1021/acsmedchemlett.7b00239

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6b2q"

Categories: Large Structures | Mycobacterium tuberculosis | Zuccola HJ

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 6b2q is ON HOLD
+==Dual Inhibition of the Essential Protein Kinases A and B in Mycobacterium tuberculosis==
+<StructureSection load='6b2q' size='340' side='right'caption='[[6b2q]], [[Resolution|resolution]] 2.88&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[6b2q]] is a 4 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=6B2Q OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6B2Q FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.88&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0BD:3-METHYL-1-(2-METHYLPROPYL)BUTYL+4-O-BETA-L-GULOPYRANOSYL-BETA-D-GLUCOPYRANOSIDE'>0BD</scene>, <scene name='pdbligand=CJJ:5-[5-chloranyl-4-[(5-cyclopropyl-1~{H}-pyrazol-3-yl)amino]pyrimidin-2-yl]thiophene-2-sulfonamide'>CJJ</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></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=6b2q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6b2q OCA], [https://pdbe.org/6b2q PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6b2q RCSB], [https://www.ebi.ac.uk/pdbsum/6b2q PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6b2q ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/PKNA_MYCTU PKNA_MYCTU] Key component of a signal transduction pathway that regulates cell growth and cell division via phosphorylation of target proteins such as FtsZ, Wag31, GlmU, FhaB, PstP, EmbR and Rv1422. Shows a strong preference for Thr versus Ser as the phosphoacceptor.<ref>PMID:15985609</ref> <ref>PMID:16817899</ref> <ref>PMID:19121323</ref> <ref>PMID:20066037</ref> <ref>PMID:21190553</ref> <ref>PMID:21423706</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.
-Authors: Zuccola, H.J., Zuccola, H.J.
+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>
-Description: Dual Inhibition of the Essential Protein Kinases A and B in Mycobacterium tuberculosis
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Zuccola, H.J]]
+<div class="pdbe-citations 6b2q" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Large Structures]]
+[[Category: Mycobacterium tuberculosis]]
+[[Category: Zuccola HJ]]

6b2q

From Proteopedia

Current revision

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

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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