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6ex7

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<StructureSection load='6ex7' size='340' side='right' caption='[[6ex7]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
<StructureSection load='6ex7' size='340' side='right' caption='[[6ex7]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[6ex7]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6EX7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6EX7 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[6ex7]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_pneumoniae"_(schroeter_1886)_flugge_1886 "bacillus pneumoniae" (schroeter 1886) flugge 1886]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6EX7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6EX7 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CD:CADMIUM+ION'>CD</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=TOE:2-[2-(2-METHOXY-ETHOXY)-ETHOXY]-ETHOXYL'>TOE</scene>, <scene name='pdbligand=UNL:UNKNOWN+LIGAND'>UNL</scene></td></tr>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CD:CADMIUM+ION'>CD</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=TOE:2-[2-(2-METHOXY-ETHOXY)-ETHOXY]-ETHOXYL'>TOE</scene>, <scene name='pdbligand=UNL:UNKNOWN+LIGAND'>UNL</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4hky|4hky]]</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4hky|4hky]]</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">blaNDM-1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=573 "Bacillus pneumoniae" (Schroeter 1886) Flugge 1886])</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[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] </span></td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[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] </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=6ex7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ex7 OCA], [http://pdbe.org/6ex7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ex7 RCSB], [http://www.ebi.ac.uk/pdbsum/6ex7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ex7 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=6ex7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ex7 OCA], [http://pdbe.org/6ex7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ex7 RCSB], [http://www.ebi.ac.uk/pdbsum/6ex7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ex7 ProSAT]</span></td></tr>
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<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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Resistance to beta-lactam antibiotics can be mediated by metallo-beta-lactamase enzymes (MBLs). An MBL inhibitor could restore the effectiveness of beta-lactams. We report on the evaluation of approved thiol-containing drugs as inhibitors of NDM-1, VIM-1, and IMP-7. Drugs were assessed by a novel assay using a purchasable fluorescent substrate and thermal shift. Best compounds were tested in antimicrobial susceptibility assay. Using these orthogonal screening methods, we identified drugs that restored the activity of imipenem.
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The specter of a return to an era in which infectious disease looms as a significant threat to human health is not just hyperbole; there are serious concerns about the widespread overuse and misuse of antibiotics contributing to increased antibiotic resistance in pathogens. The recent discovery of a new enzyme, first identified in Klebsiella pneumoniae from a patient from New Delhi and denoted as NDM-1, represents an example of extreme promiscuity: It hydrolyzes and inactivates nearly all known beta-lactam-based antibiotics with startling efficiency. NDM-1 can utilize different metal cofactors and seems to exploit an alternative mechanism based on the reaction conditions. Here we report the results of a combined experimental and theoretical study that examines the substrate, metal binding, and catalytic mechanism of the enzyme. We utilize structures obtained through X-ray crystallography, biochemical assays, and numerical simulation to construct a model of the enzyme catalytic pathway. The NDM-1 enzyme interacts with the substrate solely through zinc, or other metals, bound in the active site, explaining the observed lack of specificity against a broad range of beta-lactam antibiotic agents. The zinc ions also serve to activate a water molecule that hydrolyzes the beta-lactam ring through a proton shuttle.
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Approved Drugs Containing Thiols as Inhibitors of Metallo-beta-lactamases: Strategy To Combat Multidrug-Resistant Bacteria.,Klingler FM, Wichelhaus TA, Frank D, Cuesta-Bernal J, El-Delik J, Muller HF, Sjuts H, Gottig S, Koenigs A, Pos KM, Pogoryelov D, Proschak E J Med Chem. 2015 Apr 23;58(8):3626-30. doi: 10.1021/jm501844d. Epub 2015 Apr 13. PMID:25815530<ref>PMID:25815530</ref>
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NDM-1, the ultimate promiscuous enzyme: substrate recognition and catalytic mechanism.,Kim Y, Cunningham MA, Mire J, Tesar C, Sacchettini J, Joachimiak A FASEB J. 2013 May;27(5):1917-27. doi: 10.1096/fj.12-224014. Epub 2013 Jan 30. PMID:23363572<ref>PMID:23363572</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
</div>
<div class="pdbe-citations 6ex7" style="background-color:#fffaf0;"></div>
<div class="pdbe-citations 6ex7" style="background-color:#fffaf0;"></div>
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==See Also==
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*[[Beta-lactamase|Beta-lactamase]]
== References ==
== References ==
<references/>
<references/>

Revision as of 06:07, 25 April 2018

Crystal structure of NDM-1 metallo-beta-lactamase in complex with Cd ions and a hydrolyzed beta-lactam ligand - new refinement

6ex7, resolution 1.95Å

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