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| | ==Crystal structure of S. aureus Pyruvate Kinase== | | ==Crystal structure of S. aureus Pyruvate Kinase== |
| - | <StructureSection load='3t0t' size='340' side='right' caption='[[3t0t]], [[Resolution|resolution]] 3.10Å' scene=''> | + | <StructureSection load='3t0t' size='340' side='right'caption='[[3t0t]], [[Resolution|resolution]] 3.10Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3t0t]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Staphylococcus_aureus_subsp._aureus Staphylococcus aureus subsp. aureus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3T0T OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3T0T FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3t0t]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Staphylococcus_aureus_subsp._aureus_MRSA252 Staphylococcus aureus subsp. aureus MRSA252]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3T0T OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3T0T FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=I30:N-[(1E)-1-(1H-BENZIMIDAZOL-2-YL)ETHYLIDENE]-5-BROMO-2-HYDROXYBENZOHYDRAZIDE'>I30</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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]] 3.1Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3t05|3t05]], [[3t07|3t07]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=I30:N-[(1E)-1-(1H-BENZIMIDAZOL-2-YL)ETHYLIDENE]-5-BROMO-2-HYDROXYBENZOHYDRAZIDE'>I30</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">pyk, SAR1776 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=46170 Staphylococcus aureus subsp. aureus])</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=3t0t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3t0t OCA], [https://pdbe.org/3t0t PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3t0t RCSB], [https://www.ebi.ac.uk/pdbsum/3t0t PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3t0t ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Pyruvate_kinase Pyruvate kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.40 2.7.1.40] </span></td></tr>
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| - | <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=3t0t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3t0t OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3t0t RCSB], [http://www.ebi.ac.uk/pdbsum/3t0t PDBsum]</span></td></tr> | + | |
| | </table> | | </table> |
| - | <div style="background-color:#fffaf0;">
| + | == Function == |
| - | == Publication Abstract from PubMed == | + | [https://www.uniprot.org/uniprot/KPYK_STAAR KPYK_STAAR] |
| - | We have recently mapped the protein interaction network of methicillin-resistant Staphylococcus aureus (MRSA), which revealed its scale-free organization with characteristic presence of highly connected hub proteins that are critical for bacterial survival. Here we report the discovery of inhibitors that are highly potent against one such hub target, staphylococcal pyruvate kinase (PK). Importantly, the developed compounds demonstrate complete selectivity for the bacterial enzyme compared to all human orthologues. The lead 91nM inhibitor IS-130 has been identified through ligand-based cheminformatic exploration of a chemical space around micromolar hits initially generated by experimental screening. The following crystallographic study resulted in identification of a tetrameric MRSA PK structure where IS-130 is bound to the interface between the protein's subunits. This newly described binding pocket is not present in otherwise highly similar human orthologues and can be effectively utilized for selective inhibition of bacterial PK. The following synthetic modifications of IS-130, guided by structure-based molecular modeling, resulted in the development of MRSA PK inhibitors with much improved antimicrobial properties. Considering a notable lack of recent reports on novel antibacterial targets and cognate antibacterial compounds, this study provides a valuable perspective on the development of a new generation of antimicrobials. Equally noteworthy, the results of the current work highlight the importance of rigorous cheminformatics-based exploration of the results of high-throughput experiments.
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| - | Cheminformatics-driven discovery of selective, nanomolar inhibitors for staphylococcal pyruvate kinase.,Axerio-Cilies P, See RH, Zoraghi R, Worral L, Lian T, Stoynov N, Jiang J, Kaur S, Jackson L, Gong H, Swayze R, Amandoron E, Kumar NS, Moreau A, Hsing M, Strynadka NC, McMaster WR, Finlay BB, Foster LJ, Young RN, Reiner NE, Cherkasov A ACS Chem Biol. 2012 Feb 17;7(2):350-9. doi: 10.1021/cb2003576. Epub 2011 Nov 21. PMID:22066782<ref>PMID:22066782</ref>
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| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| - | </div>
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| | ==See Also== | | ==See Also== |
| - | *[[Pyruvate Kinase|Pyruvate Kinase]] | + | *[[Pyruvate kinase 3D structures|Pyruvate kinase 3D structures]] |
| - | == References ==
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| - | <references/>
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Pyruvate kinase]] | + | [[Category: Large Structures]] |
| - | [[Category: Staphylococcus aureus subsp. aureus]] | + | [[Category: Staphylococcus aureus subsp. aureus MRSA252]] |
| - | [[Category: Strynadka, N C.J]] | + | [[Category: Strynadka NCJ]] |
| - | [[Category: Vuckovic, M]] | + | [[Category: Vuckovic M]] |
| - | [[Category: Worrall, L J]] | + | [[Category: Worrall LJ]] |
| - | [[Category: Ligand]]
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| - | [[Category: Tetramer]]
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| - | [[Category: Transferase-transferase inhibitor complex]]
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