2qdt

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[[Image:2qdt.jpg|left|200px]]<br /><applet load="2qdt" size="350" color="white" frame="true" align="right" spinBox="true"
 
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caption="2qdt, resolution 2.00&Aring;" />
 
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'''Structural Basis for the Broad-Spectrum Inhibition of Metallo-{Beta}-Lactamases: L1- IS38 Complex'''<br />
 
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==Overview==
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==Structural Basis for the Broad-Spectrum Inhibition of Metallo-{Beta}-Lactamases: L1- IS38 Complex==
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Various inhibitors of metallo-beta-lactamases have been reported, however, none are effective for all subgroups. Those that have been found to, inhibit the enzymes of subclass B2 (catalytically active with one zinc), either contain a thiol (and show less inhibition towards this subgroup, than towards the dizinc members of B1 and B3) or are inactivators behaving, as substrates for the dizinc family members. The present work reveals that, certain pyridine carboxylates are competitive inhibitors of CphA, a, subclass B2 enzyme. X-ray crystallographic analyses demonstrate that, pyridine-2,4-dicarboxylic acid chelates the zinc ion in a bidentate manner, within the active site. Salts of these compounds are already available and, undergoing biomedical testing for various non-related purposes., Pyridine-carboxylates appear useful templates for the development of more, complex, selective, non-toxic inhibitors of the subclass B2, metallo-beta-lactamases.
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<StructureSection load='2qdt' size='340' side='right'caption='[[2qdt]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2qdt]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Stenotrophomonas_maltophilia Stenotrophomonas maltophilia]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2QDT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2QDT FirstGlance]. <br>
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</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&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=I38:N-(3-MERCAPTOPROPANOYL)-D-ALANINE'>I38</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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=2qdt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2qdt OCA], [https://pdbe.org/2qdt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2qdt RCSB], [https://www.ebi.ac.uk/pdbsum/2qdt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2qdt ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/BLA1_STEMA BLA1_STEMA] Has a high activity against imipenem.
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/qd/2qdt_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2qdt ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The development of broad-spectrum metallo-beta-lactamase (MBL) inhibitors is challenging due to structural diversity and differences in metal utilisation by these enzymes. Analysis of structural data, followed by non-denturing mass spectrometric analyses, identified thiols proposed to inhibit representative MBLs from all three sub-classes: B1, B2 and B3. Solution analyses led to the identification of broad spectrum inhibitors, including potent inhibitors of the CphA MBL (Aeromonas hydrophila). Structural studies revealed that, as observed for other B1 and B3 MBLs, inhibition of the L1 MBL thiols involves metal chelation. Evidence is reported that this is not the case for inhibition of the CphA enzyme by some thiols; the crystal structure of the CphA-Zn-inhibitor complex reveals a binding mode in which the thiol does not interact with the zinc. The structural data enabled the design and the production of further more potent inhibitors. Overall the results suggest that the development of reasonably broad-spectrum MBL inhibitors should be possible.
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==About this Structure==
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Structural basis for the broad-spectrum inhibition of metallo-beta-lactamases by thiols.,Lienard BM, Garau G, Horsfall L, Karsisiotis AI, Damblon C, Lassaux P, Papamicael C, Roberts GC, Galleni M, Dideberg O, Frere JM, Schofield CJ Org Biomol Chem. 2008 Jul 7;6(13):2282-94. Epub 2008 May 7. PMID:18563261<ref>PMID:18563261</ref>
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2QDT is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Stenotrophomonas_maltophilia Stenotrophomonas maltophilia] with <scene name='pdbligand=ZN:'>ZN</scene>, <scene name='pdbligand=SO4:'>SO4</scene> and <scene name='pdbligand=I38:'>I38</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Beta-lactamase Beta-lactamase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.2.6 3.5.2.6] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2QDT OCA].
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==Reference==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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Competitive Inhibitors of the CphA Metallo-{beta}-Lactamase from Aeromonas hydrophila., Horsfall LE, Garau G, Lienard BM, Dideberg O, Schofield CJ, Frere JM, Galleni M, Antimicrob Agents Chemother. 2007 Feb 16;. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17307979 17307979]
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</div>
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[[Category: Beta-lactamase]]
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<div class="pdbe-citations 2qdt" style="background-color:#fffaf0;"></div>
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[[Category: Single protein]]
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[[Category: Stenotrophomonas maltophilia]]
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[[Category: Dideberg, O.]]
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[[Category: Garau, G.]]
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[[Category: I38]]
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[[Category: SO4]]
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[[Category: ZN]]
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[[Category: hydrolase]]
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[[Category: inhibitor]]
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[[Category: l1]]
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[[Category: lactamase]]
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[[Category: metallo]]
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[[Category: zn]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 13:52:39 2008''
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==See Also==
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*[[Beta-lactamase 3D structures|Beta-lactamase 3D structures]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Large Structures]]
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[[Category: Stenotrophomonas maltophilia]]
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[[Category: Dideberg O]]
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[[Category: Garau G]]

Current revision

Structural Basis for the Broad-Spectrum Inhibition of Metallo-{Beta}-Lactamases: L1- IS38 Complex

PDB ID 2qdt

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