4y0x: Difference between revisions

Revision as of 23:40, 5 June 2019

Crystal structure of the S/T protein kinase PknG from Mycobacterium tuberculosis in complex with ADP

Structural highlights

4y0x is a 1 chain structure with sequence from Myctu. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	ADP, MG, ZN
Gene:	pknG, Rv0410c, MTCY22G10.06c (MYCTU)
Activity:	Non-specific serine/threonine protein kinase, with EC number 2.7.11.1
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[PKNG_MYCTU] Phosphorylates GarA. May play a role in metabolic regulation via control of the phosphorylation status of GarA. Plays a crucial role in the survival of mycobacteria within host macrophages, by blocking the intracellular degradation of mycobacteria in lysosomes. Required for intrinsic antibiotic resistance.^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

Tuberculosis remains one of the world's deadliest human diseases, with a high prevalence of antibiotic-resistant Mycobacterium tuberculosis (Mtb) strains. A molecular understanding of processes underlying regulation and adaptation of bacterial physiology may provide novel avenues for the development of antibiotics with unconventional modes of action. Here, we focus on the multidomain S/T protein kinase PknG, a soluble enzyme that controls central metabolism in Actinobacteria and has been linked to Mtb infectivity. Our biochemical and structural studies reveal how different motifs and domains flanking the catalytic core regulate substrate selectivity without significantly affecting the intrinsic kinase activity, whereas a rubredoxin-like domain is shown to downregulate catalysis through specific intramolecular interactions that modulate access to a profound substrate-binding site. Our findings provide the basis for the selective and specific inhibition of PknG, and open new questions about regulation of related bacterial and eukaryotic protein kinases.

Molecular Basis of the Activity and the Regulation of the Eukaryotic-like S/T Protein Kinase PknG from Mycobacterium tuberculosis.,Lisa MN, Gil M, Andre-Leroux G, Barilone N, Duran R, Biondi RM, Alzari PM Structure. 2015 Apr 29. pii: S0969-2126(15)00126-4. doi:, 10.1016/j.str.2015.04.001. PMID:25960409^[5]

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

References

↑ O'Hare HM, Duran R, Cervenansky C, Bellinzoni M, Wehenkel AM, Pritsch O, Obal G, Baumgartner J, Vialaret J, Johnsson K, Alzari PM. Regulation of glutamate metabolism by protein kinases in mycobacteria. Mol Microbiol. 2008 Dec;70(6):1408-23. doi: 10.1111/j.1365-2958.2008.06489.x., Epub 2008 Oct 17. PMID:19019160 doi:https://dx.doi.org/10.1111/j.1365-2958.2008.06489.x
↑ Wolff KA, Nguyen HT, Cartabuke RH, Singh A, Ogwang S, Nguyen L. Protein kinase G is required for intrinsic antibiotic resistance in mycobacteria. Antimicrob Agents Chemother. 2009 Aug;53(8):3515-9. doi: 10.1128/AAC.00012-09., Epub 2009 Jun 15. PMID:19528288 doi:https://dx.doi.org/10.1128/AAC.00012-09
↑ Tiwari D, Singh RK, Goswami K, Verma SK, Prakash B, Nandicoori VK. Key residues in Mycobacterium tuberculosis protein kinase G play a role in regulating kinase activity and survival in the host. J Biol Chem. 2009 Oct 2;284(40):27467-79. doi: 10.1074/jbc.M109.036095. Epub 2009, Jul 28. PMID:19638631 doi:https://dx.doi.org/10.1074/jbc.M109.036095
↑ Scherr N, Honnappa S, Kunz G, Mueller P, Jayachandran R, Winkler F, Pieters J, Steinmetz MO. Structural basis for the specific inhibition of protein kinase G, a virulence factor of Mycobacterium tuberculosis. Proc Natl Acad Sci U S A. 2007 Jul 17;104(29):12151-6. Epub 2007 Jul 6. PMID:17616581
↑ Lisa MN, Gil M, Andre-Leroux G, Barilone N, Duran R, Biondi RM, Alzari PM. Molecular Basis of the Activity and the Regulation of the Eukaryotic-like S/T Protein Kinase PknG from Mycobacterium tuberculosis. Structure. 2015 Apr 29. pii: S0969-2126(15)00126-4. doi:, 10.1016/j.str.2015.04.001. PMID:25960409 doi:https://dx.doi.org/10.1016/j.str.2015.04.001

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OCA

[1] O'Hare HM, Duran R, Cervenansky C, Bellinzoni M, Wehenkel AM, Pritsch O, Obal G, Baumgartner J, Vialaret J, Johnsson K, Alzari PM. Regulation of glutamate metabolism by protein kinases in mycobacteria. Mol Microbiol. 2008 Dec;70(6):1408-23. doi: 10.1111/j.1365-2958.2008.06489.x., Epub 2008 Oct 17. PMID:19019160 doi:https://dx.doi.org/10.1111/j.1365-2958.2008.06489.x

[2] Wolff KA, Nguyen HT, Cartabuke RH, Singh A, Ogwang S, Nguyen L. Protein kinase G is required for intrinsic antibiotic resistance in mycobacteria. Antimicrob Agents Chemother. 2009 Aug;53(8):3515-9. doi: 10.1128/AAC.00012-09., Epub 2009 Jun 15. PMID:19528288 doi:https://dx.doi.org/10.1128/AAC.00012-09

[3] Tiwari D, Singh RK, Goswami K, Verma SK, Prakash B, Nandicoori VK. Key residues in Mycobacterium tuberculosis protein kinase G play a role in regulating kinase activity and survival in the host. J Biol Chem. 2009 Oct 2;284(40):27467-79. doi: 10.1074/jbc.M109.036095. Epub 2009, Jul 28. PMID:19638631 doi:https://dx.doi.org/10.1074/jbc.M109.036095

[4] Scherr N, Honnappa S, Kunz G, Mueller P, Jayachandran R, Winkler F, Pieters J, Steinmetz MO. Structural basis for the specific inhibition of protein kinase G, a virulence factor of Mycobacterium tuberculosis. Proc Natl Acad Sci U S A. 2007 Jul 17;104(29):12151-6. Epub 2007 Jul 6. PMID:17616581

[5] Lisa MN, Gil M, Andre-Leroux G, Barilone N, Duran R, Biondi RM, Alzari PM. Molecular Basis of the Activity and the Regulation of the Eukaryotic-like S/T Protein Kinase PknG from Mycobacterium tuberculosis. Structure. 2015 Apr 29. pii: S0969-2126(15)00126-4. doi:, 10.1016/j.str.2015.04.001. PMID:25960409 doi:https://dx.doi.org/10.1016/j.str.2015.04.001

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@@ Line 1: / Line 1: @@
 ==Crystal structure of the S/T protein kinase PknG from Mycobacterium tuberculosis in complex with ADP==
-<StructureSection load='4y0x' size='340' side='right' caption='[[4y0x]], [[Resolution|resolution]] 1.74&Aring;' scene=''>
+<StructureSection load='4y0x' size='340' side='right'caption='[[4y0x]], [[Resolution|resolution]] 1.74&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4y0x]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4Y0X OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4Y0X FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4y0x]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Myctu Myctu]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4Y0X OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4Y0X FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">pknG, Rv0410c, MTCY22G10.06c ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=83332 MYCTU])</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4y0x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4y0x OCA], [http://pdbe.org/4y0x PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4y0x RCSB], [http://www.ebi.ac.uk/pdbsum/4y0x PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4y0x ProSAT]</span></td></tr>
@@ Line 26: / Line 27: @@
 __TOC__
 </StructureSection>
+[[Category: Large Structures]]
+[[Category: Myctu]]
 [[Category: Non-specific serine/threonine protein kinase]]
 [[Category: Alzari, P M]]

4y0x: Difference between revisions

Revision as of 23:40, 5 June 2019

Crystal structure of the S/T protein kinase PknG from Mycobacterium tuberculosis in complex with ADP

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

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