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| | ==Crystal structure of kinase domain of PknA from Mtb== | | ==Crystal structure of kinase domain of PknA from Mtb== |
| - | <StructureSection load='4ow8' size='340' side='right' caption='[[4ow8]], [[Resolution|resolution]] 2.03Å' scene=''> | + | <StructureSection load='4ow8' size='340' side='right'caption='[[4ow8]], [[Resolution|resolution]] 2.03Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4ow8]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_tuberculosis"_(zopf_1883)_klein_1884 "bacillus tuberculosis" (zopf 1883) klein 1884]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4OW8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4OW8 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4ow8]] 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=4OW8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4OW8 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 2.03Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MT0018,MTCY10H4.15c,RV0015c,pknA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1773 "Bacillus tuberculosis" (Zopf 1883) Klein 1884])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4ow8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ow8 OCA], [https://pdbe.org/4ow8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ow8 RCSB], [https://www.ebi.ac.uk/pdbsum/4ow8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ow8 ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ow8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ow8 OCA], [http://pdbe.org/4ow8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ow8 RCSB], [http://www.ebi.ac.uk/pdbsum/4ow8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4ow8 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://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> | + | [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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 4ow8" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 4ow8" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Non-specific serine/threonine protein kinase]] | + | [[Category: Large Structures]] |
| - | [[Category: Chakraborti, P K]] | + | [[Category: Mycobacterium tuberculosis]] |
| - | [[Category: Karthikeyan, S]] | + | [[Category: Chakraborti PK]] |
| - | [[Category: Ravala, S K]] | + | [[Category: Karthikeyan S]] |
| - | [[Category: Singh, S]] | + | [[Category: Ravala SK]] |
| - | [[Category: Yadav, G S]] | + | [[Category: Singh S]] |
| - | [[Category: Drug target]] | + | [[Category: Yadav GS]] |
| - | [[Category: Kinase]]
| + | |
| - | [[Category: Mtb]]
| + | |
| - | [[Category: Pkna]]
| + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
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
Phosphorylation of the activation loop in the catalytic domain of the RD family of bacterial eukaryotic-type Ser/Thr protein kinases (STPK) induces their conformational transition from an inactive to active state. However, mechanistic insights into the phosphorylation-mediated transition of these STPKs from an inactive to active state remain unknown. In the present study, we addressed this issue with PknA, an essential STPK from Mycobacterium tuberculosis. We found that the catalytic activity of PknA is confined within the N-terminal 283 amino acids (PknA-283). The crystal structure of PknA-283 in unphosphorylated form showed an ordered activation loop and existed in an inactive state preventing the phosphorylation of its cognate substrate(s). Peptide mass finger printing studies revealed that all activation loop threonines (Thr172, Thr174 and Thr180) were phosphorylated in the activated PknA-283 protein. Substitution of Thr180 with Ala/Asp (T180A/T180D) resulted in catalytically defective mutants, whereas a double mutant replacing Thr172 and Thr174 with Ala (T172A-T174A) was deficient in kinase activity. Analysis of PknA-283 structure, together with biochemical studies, revealed the possibility of phosphorylation of Thr180 via a cis mechanism, whereas that of Thr172 and Thr174 occurs via a trans mechanism. Moreover, unlike wild-type, these mutants did not show any drastic change in cell morphology in a phenotypic assay, implicating the role of all threonines in the activation loop towards the functionality of PknA. Thus, our findings offer a model for kinase activation showing that the phosphorylation of Thr180 triggers PknA to transphosphorylate Thr172/Thr174, thereby governing its functionality.
Evidence that phosphorylation of threonine in the GT motif triggers activation of PknA, a eukaryotic-type serine/threonine kinase from Mycobacterium tuberculosis.,Ravala SK, Singh S, Yadav GS, Kumar S, Karthikeyan S, Chakraborti PK FEBS J. 2015 Feb 9. doi: 10.1111/febs.13230. PMID:25665034[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
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
- ↑ Ravala SK, Singh S, Yadav GS, Kumar S, Karthikeyan S, Chakraborti PK. Evidence that phosphorylation of threonine in the GT motif triggers activation of PknA, a eukaryotic-type serine/threonine kinase from Mycobacterium tuberculosis. FEBS J. 2015 Feb 9. doi: 10.1111/febs.13230. PMID:25665034 doi:http://dx.doi.org/10.1111/febs.13230
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