5y6e: Difference between revisions
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<StructureSection load='5y6e' size='340' side='right' caption='[[5y6e]], [[Resolution|resolution]] 1.80Å' scene=''> | <StructureSection load='5y6e' size='340' side='right' caption='[[5y6e]], [[Resolution|resolution]] 1.80Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5y6e]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5Y6E OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5Y6E FirstGlance]. <br> | <table><tr><td colspan='2'>[[5y6e]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_aeruginosus"_(schroeter_1872)_trevisan_1885 "bacillus aeruginosus" (schroeter 1872) trevisan 1885]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5Y6E OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5Y6E FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=8PO:(2R)-2-(4-hydroxyphenyl)-2-[[(2S)-2-methyl-3-sulfanyl-propanoyl]amino]ethanoic+acid'>8PO</scene>, <scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=8PO:(2R)-2-(4-hydroxyphenyl)-2-[[(2S)-2-methyl-3-sulfanyl-propanoyl]amino]ethanoic+acid'>8PO</scene>, <scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">blaVIM-2, bla vim-2, bla-VIM-2, blasVIM-2, blaVIM2, blm, VIM-2, vim-2, PAERUG_P32_London_17_VIM_2_10_11_06255 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=287 "Bacillus aeruginosus" (Schroeter 1872) Trevisan 1885])</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=5y6e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5y6e OCA], [http://pdbe.org/5y6e PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5y6e RCSB], [http://www.ebi.ac.uk/pdbsum/5y6e PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5y6e 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=5y6e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5y6e OCA], [http://pdbe.org/5y6e PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5y6e RCSB], [http://www.ebi.ac.uk/pdbsum/5y6e PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5y6e ProSAT]</span></td></tr> | ||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The emergence and global spread of metallo-beta-lactamase (MBL) mediated resistance to almost all beta-lactam antibacterials poses a serious threat to public health. Since no clinically useful MBL inhibitors have been reported, there is an urgent need to develop new potent broad-spectrum MBL inhibitors effective against antibacterial resistance. Herein, we synthesized a set of 2-substituted ((S)-3-mercapto-2-methylpropanamido) acetic acid derivatives, some of which displayed potent inhibition with high ligand efficiency to the clinically relevant MBL subtypes, Verona Integron-encoded MBL (VIM)-2 and New Delhi MBL (NDM)-1. Kinetic studies revealed that the inhibitors are not strong zinc chelators in solution, and they bind reversibly to VIM-2 but dissociate very slowly. Crystallographic analyses revealed that they inhibit VIM-2 via chelating the active site zinc ions and interacting with catalytically important residues. Further cell- and zebrafish-based assays revealed that the inhibitors slightly increase susceptibility of E. coli cells expressing VIM-2 to meropenem, and they have no apparent toxicity to the viability of HEK293T cells and the zebrafish embryogenesis. | |||
((S)-3-Mercapto-2-methylpropanamido)acetic acid derivatives as metallo-beta-lactamase inhibitors: Synthesis, kinetic and crystallographic studies.,Liu S, Jing L, Yu ZJ, Wu C, Zheng Y, Zhang E, Chen Q, Yu Y, Guo L, Wu Y, Li GB Eur J Med Chem. 2018 Feb 10;145:649-660. doi: 10.1016/j.ejmech.2018.01.032. Epub , 2018 Jan 11. PMID:29353720<ref>PMID:29353720</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 5y6e" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
Revision as of 09:46, 7 February 2018
VIM-2 metallo-beta-lactamase in complex with (R)-2-(4-hydroxyphenyl)-2-((S)-3-mercapto-2-methylpropanamido)acetic acid (compound 12)VIM-2 metallo-beta-lactamase in complex with (R)-2-(4-hydroxyphenyl)-2-((S)-3-mercapto-2-methylpropanamido)acetic acid (compound 12)
Structural highlights
Publication Abstract from PubMedThe emergence and global spread of metallo-beta-lactamase (MBL) mediated resistance to almost all beta-lactam antibacterials poses a serious threat to public health. Since no clinically useful MBL inhibitors have been reported, there is an urgent need to develop new potent broad-spectrum MBL inhibitors effective against antibacterial resistance. Herein, we synthesized a set of 2-substituted ((S)-3-mercapto-2-methylpropanamido) acetic acid derivatives, some of which displayed potent inhibition with high ligand efficiency to the clinically relevant MBL subtypes, Verona Integron-encoded MBL (VIM)-2 and New Delhi MBL (NDM)-1. Kinetic studies revealed that the inhibitors are not strong zinc chelators in solution, and they bind reversibly to VIM-2 but dissociate very slowly. Crystallographic analyses revealed that they inhibit VIM-2 via chelating the active site zinc ions and interacting with catalytically important residues. Further cell- and zebrafish-based assays revealed that the inhibitors slightly increase susceptibility of E. coli cells expressing VIM-2 to meropenem, and they have no apparent toxicity to the viability of HEK293T cells and the zebrafish embryogenesis. ((S)-3-Mercapto-2-methylpropanamido)acetic acid derivatives as metallo-beta-lactamase inhibitors: Synthesis, kinetic and crystallographic studies.,Liu S, Jing L, Yu ZJ, Wu C, Zheng Y, Zhang E, Chen Q, Yu Y, Guo L, Wu Y, Li GB Eur J Med Chem. 2018 Feb 10;145:649-660. doi: 10.1016/j.ejmech.2018.01.032. Epub , 2018 Jan 11. PMID:29353720[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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