6eum: Difference between revisions
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==CRYSTAL STRUCTURE OF BCII METALLO-BETA-LACTAMASE IN COMPLEX WITH DZ-307== | |||
<StructureSection load='6eum' size='340' side='right' caption='[[6eum]], [[Resolution|resolution]] 1.18Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6eum]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6EUM OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6EUM FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BY5:(~{Z})-2-sulfanyl-3-[2,3,6-tris(fluoranyl)phenyl]prop-2-enoic+acid'>BY5</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | |||
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=CSO:S-HYDROXYCYSTEINE'>CSO</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5jmx|5jmx]], [[4tyt|4tyt]]</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=6eum FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6eum OCA], [http://pdbe.org/6eum PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6eum RCSB], [http://www.ebi.ac.uk/pdbsum/6eum PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6eum ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/BLA2_BACCE BLA2_BACCE]] Can hydrolyze carbapenem compounds. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Metallo-beta-lactamases (MBLs) enable bacterial resistance to almost all classes of beta-lactam antibiotics. We report studies on enethiol containing MBL inhibitors, which were prepared by rhodanine hydrolysis. The enethiols inhibit MBLs from different subclasses. Crystallographic analyses reveal that the enethiol sulphur displaces the di-Zn(II) ion bridging 'hydrolytic' water. In some, but not all, cases biophysical analyses provide evidence that rhodanine/enethiol inhibition involves formation of a ternary MBL enethiol rhodanine complex. The results demonstrate how low molecular weight active site Zn(II) chelating compounds can inhibit a range of clinically relevant MBLs and provide additional evidence for the potential of rhodanines to be hydrolysed to potent inhibitors of MBL protein fold and, maybe, other metallo-enzymes, perhaps contributing to the complex biological effects of rhodanines. The results imply that any medicinal chemistry studies employing rhodanines (and related scaffolds) as inhibitors should as a matter of course include testing of their hydrolysis products. | |||
Structure activity relationship studies on rhodanines and derived enethiol inhibitors of metallo-beta-lactamases.,Zhang D, Markoulides MS, Stepanovs D, Rydzik AM, El-Hussein A, Bon C, Kamps JJAG, Umland KD, Collins PM, Cahill ST, Wang DY, von Delft F, Brem J, McDonough MA, Schofield CJ Bioorg Med Chem. 2018 Jul 15;26(11):2928-2936. doi: 10.1016/j.bmc.2018.02.043., Epub 2018 Feb 23. PMID:29655609<ref>PMID:29655609</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 6eum" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Beta-lactamase]] | |||
[[Category: Brem, J]] | |||
[[Category: El-Husseiny, A]] | |||
[[Category: McDonough, M A]] | |||
[[Category: Schofield, C J]] | |||
[[Category: Stepanovs, D]] | |||
[[Category: Zhang, D]] | |||
[[Category: Antimicrobial resistance]] | |||
[[Category: Hydrolase]] | |||
[[Category: Inhibitor]] | |||
[[Category: Metallo beta lactamase]] | |||
Latest revision as of 10:49, 3 October 2018
CRYSTAL STRUCTURE OF BCII METALLO-BETA-LACTAMASE IN COMPLEX WITH DZ-307CRYSTAL STRUCTURE OF BCII METALLO-BETA-LACTAMASE IN COMPLEX WITH DZ-307
Structural highlights
Function[BLA2_BACCE] Can hydrolyze carbapenem compounds. Publication Abstract from PubMedMetallo-beta-lactamases (MBLs) enable bacterial resistance to almost all classes of beta-lactam antibiotics. We report studies on enethiol containing MBL inhibitors, which were prepared by rhodanine hydrolysis. The enethiols inhibit MBLs from different subclasses. Crystallographic analyses reveal that the enethiol sulphur displaces the di-Zn(II) ion bridging 'hydrolytic' water. In some, but not all, cases biophysical analyses provide evidence that rhodanine/enethiol inhibition involves formation of a ternary MBL enethiol rhodanine complex. The results demonstrate how low molecular weight active site Zn(II) chelating compounds can inhibit a range of clinically relevant MBLs and provide additional evidence for the potential of rhodanines to be hydrolysed to potent inhibitors of MBL protein fold and, maybe, other metallo-enzymes, perhaps contributing to the complex biological effects of rhodanines. The results imply that any medicinal chemistry studies employing rhodanines (and related scaffolds) as inhibitors should as a matter of course include testing of their hydrolysis products. Structure activity relationship studies on rhodanines and derived enethiol inhibitors of metallo-beta-lactamases.,Zhang D, Markoulides MS, Stepanovs D, Rydzik AM, El-Hussein A, Bon C, Kamps JJAG, Umland KD, Collins PM, Cahill ST, Wang DY, von Delft F, Brem J, McDonough MA, Schofield CJ Bioorg Med Chem. 2018 Jul 15;26(11):2928-2936. doi: 10.1016/j.bmc.2018.02.043., Epub 2018 Feb 23. PMID:29655609[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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