5u94

From Proteopedia

(Difference between revisions)
Jump to: navigation, search
Current revision (13:23, 4 October 2023) (edit) (undo)
 
(2 intermediate revisions not shown.)
Line 1: Line 1:
==Crystal structure of the Mycobacterium tuberculosis PASTA kinase PknB in complex with the potential theraputic kinase inhibitor GSK690693.==
==Crystal structure of the Mycobacterium tuberculosis PASTA kinase PknB in complex with the potential theraputic kinase inhibitor GSK690693.==
-
<StructureSection load='5u94' size='340' side='right' caption='[[5u94]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
+
<StructureSection load='5u94' size='340' side='right'caption='[[5u94]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
-
<table><tr><td colspan='2'>[[5u94]] 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=5U94 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5U94 FirstGlance]. <br>
+
<table><tr><td colspan='2'>[[5u94]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis_H37Rv Mycobacterium tuberculosis H37Rv]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5U94 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5U94 FirstGlance]. <br>
-
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=G93:4-{2-(4-AMINO-1,2,5-OXADIAZOL-3-YL)-1-ETHYL-7-[(3S)-PIPERIDIN-3-YLMETHOXY]-1H-IMIDAZO[4,5-C]PYRIDIN-4-YL}-2-METHYLBUT-3-YN-2-OL'>G93</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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]] 2.2&#8491;</td></tr>
-
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">pknB, Rv0014c, MTCY10H4.14c ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=83332 MYCTU])</td></tr>
+
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=G93:4-{2-(4-AMINO-1,2,5-OXADIAZOL-3-YL)-1-ETHYL-7-[(3S)-PIPERIDIN-3-YLMETHOXY]-1H-IMIDAZO[4,5-C]PYRIDIN-4-YL}-2-METHYLBUT-3-YN-2-OL'>G93</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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=5u94 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5u94 OCA], [https://pdbe.org/5u94 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5u94 RCSB], [https://www.ebi.ac.uk/pdbsum/5u94 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5u94 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=5u94 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5u94 OCA], [http://pdbe.org/5u94 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5u94 RCSB], [http://www.ebi.ac.uk/pdbsum/5u94 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5u94 ProSAT]</span></td></tr>
+
</table>
</table>
== Function ==
== Function ==
-
[[http://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>
+
[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 ==
 +
New tools and concepts are needed to combat antimicrobial resistance. Actinomycetes and firmicutes share several eukaryotic-like Ser/Thr kinases (eSTK) that offer antibiotic development opportunities, including PknB, an essential mycobacterial eSTK. Despite successful development of potent biochemical PknB inhibitors by many groups, clinically useful microbiologic activity has been elusive. Additionally, PknB kinetics are not fully described, nor are structures with specific inhibitors available to inform inhibitor design. We used computational modeling with available structural information to identify human kinase inhibitors predicted to bind PknB, and we selected hits based on drug-like characteristics intended to increase the likelihood of cell entry. The computational model suggested a family of inhibitors, the imidazopyridine aminofurazans (IPAs), bind PknB with high affinity. We performed an in-depth characterization of PknB and found that these inhibitors biochemically inhibit PknB, with potency roughly following the predicted models. A novel X-ray structure confirmed that the inhibitors bound as predicted and made favorable protein contacts with the target. These inhibitors also have antimicrobial activity toward mycobacteria and nocardia. We demonstrated that the inhibitors are uniquely potentiated by beta-lactams but not antibiotics traditionally used to treat mycobacteria, consistent with PknB's role in sensing cell wall stress. This is the first demonstration in the phylum actinobacteria that some beta-lactam antibiotics could be more effective if paired with a PknB inhibitor. Collectively, our data show that in silico modeling can be used as a tool to discover promising drug leads, and the inhibitors we discovered can act with clinically relevant antibiotics to restore their efficacy against bacteria with limited treatment options.
 +
 
 +
In Silico Screen and Structural Analysis Identifies Bacterial Kinase Inhibitors which Act with beta-Lactams To Inhibit Mycobacterial Growth.,Wlodarchak N, Teachout N, Beczkiewicz J, Procknow R, Schaenzer AJ, Satyshur K, Pavelka M, Zuercher W, Drewry D, Sauer JD, Striker R Mol Pharm. 2018 Nov 5;15(11):5410-5426. doi: 10.1021/acs.molpharmaceut.8b00905., Epub 2018 Oct 18. PMID:30285456<ref>PMID:30285456</ref>
 +
 
 +
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 +
</div>
 +
<div class="pdbe-citations 5u94" 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: Myctu]]
+
[[Category: Large Structures]]
-
[[Category: Non-specific serine/threonine protein kinase]]
+
[[Category: Mycobacterium tuberculosis H37Rv]]
-
[[Category: Satyshur, K]]
+
[[Category: Satyshur K]]
-
[[Category: Striker, R]]
+
[[Category: Striker R]]
-
[[Category: Wlodarchak, N]]
+
[[Category: Wlodarchak N]]
-
[[Category: Inhibitor]]
+
-
[[Category: Kinase]]
+
-
[[Category: Transferase]]
+
-
[[Category: Transferase-transferase inhibitor complex]]
+

Current revision

Crystal structure of the Mycobacterium tuberculosis PASTA kinase PknB in complex with the potential theraputic kinase inhibitor GSK690693.

PDB ID 5u94

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5u94"
Personal tools