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| | <StructureSection load='3t05' size='340' side='right'caption='[[3t05]], [[Resolution|resolution]] 3.05Å' scene=''> | | <StructureSection load='3t05' size='340' side='right'caption='[[3t05]], [[Resolution|resolution]] 3.05Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3t05]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Staar Staar]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3T05 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3T05 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3t05]] 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=3T05 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3T05 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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]] 3.05Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3t07|3t07]], [[3t0t|3t0t]]</div></td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=282458 STAAR])</td></tr> | + | |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Pyruvate_kinase Pyruvate kinase], with EC number [https://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'>[https://proteopedia.org/fgij/fg.htm?mol=3t05 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3t05 OCA], [https://pdbe.org/3t05 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3t05 RCSB], [https://www.ebi.ac.uk/pdbsum/3t05 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3t05 ProSAT]</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=3t05 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3t05 OCA], [https://pdbe.org/3t05 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3t05 RCSB], [https://www.ebi.ac.uk/pdbsum/3t05 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3t05 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| - | <div style="background-color:#fffaf0;">
| + | == Function == |
| - | == Publication Abstract from PubMed == | + | [https://www.uniprot.org/uniprot/KPYK_STAAR KPYK_STAAR] |
| - | Novel classes of antimicrobials are needed to address the emergence of multidrug-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA). We have recently identified pyruvate kinase (PK) as a potential novel drug target based upon it being an essential hub in the MRSA interactome (1,2). Screening of an extract library of marine invertebrates against MRSA PK resulted in the identification of bis-indole alkaloids of the spongotine (A), topsentin (B, D) and hamacanthin (C) classes isolated from the Topsentia pachastrelloides as novel bacterial PK inhibitors. These compounds potently and selectively inhibited both MRSA PK enzymatic activity and S. aureus growth in vitro. The most active compounds cis-3,4-dihyrohyrohamacanthin B (C) and bromodexytopsentin (D) were identified as highly potent MRSA PK inhibitors (IC50 values of 16-60 nM) with at least 166-fold selectivity over human PK isoforms. These novel anti-PK natural compounds exhibited significant antibacterial activities against S. aureus, including MRSA (MICs of 12.5 and 6.25 mug/ml, respectively) with selectivity indices (CC50/MIC) > 4. We also report the discrete structural features of the MRSA PK tetramer as determined by X-ray crystallography, which is suitable for selective targeting of the bacterial enzyme. The co-crystal structure of compound C with MRSA PK confirms that the latter is a target for bis-indole alkaloids. It elucidates the essential structural requirements for PK inhibitors in small interfaces that provide for tetramer rigidity and efficient catalytic activity. Our results identified a series of natural products as novel MRSA PK inhibitors, providing the basis for further development of potential novel antimicrobials.
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| - | MRSA pyruvate kinase as a target for bis-indole alkaloids with antibacterial activities.,Zoraghi R, Warroll L, See RH, Strangman W, Popplewell WL, Gong H, Samaai T, Swayze RD, Kaur S, Vuckovic M, Finlay BB, Brunham RC, McMaster WR, Davies-Coleman MT, Strynadka NC, Andersen RJ, Reiner NE J Biol Chem. 2011 Oct 26. PMID:22030393<ref>PMID:22030393</ref>
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| - | | + | |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| - | </div>
| + | |
| - | <div class="pdbe-citations 3t05" style="background-color:#fffaf0;"></div>
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| | | | |
| | ==See Also== | | ==See Also== |
| | *[[Pyruvate kinase 3D structures|Pyruvate kinase 3D structures]] | | *[[Pyruvate kinase 3D structures|Pyruvate kinase 3D structures]] |
| - | == References == | |
| - | <references/> | |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Pyruvate kinase]] | + | [[Category: Staphylococcus aureus subsp. aureus MRSA252]] |
| - | [[Category: Staar]]
| + | [[Category: Strynadka NCJ]] |
| - | [[Category: Strynadka, N C.J]] | + | [[Category: Vuckovic M]] |
| - | [[Category: Vuckovic, M]] | + | [[Category: Worrall LJ]] |
| - | [[Category: Worrall, L J]] | + | |
| - | [[Category: Glycolysis]]
| + | |
| - | [[Category: Tetramer]]
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| - | [[Category: Transferase]]
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