6jn4: Difference between revisions
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<StructureSection load='6jn4' size='340' side='right'caption='[[6jn4]], [[Resolution|resolution]] 1.90Å' scene=''> | <StructureSection load='6jn4' size='340' side='right'caption='[[6jn4]], [[Resolution|resolution]] 1.90Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6jn4]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6JN4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6JN4 FirstGlance]. <br> | <table><tr><td colspan='2'>[[6jn4]] is a 4 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=6JN4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6JN4 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=ACY:ACETIC+ACID'>ACY</scene>, <scene name='pdbligand=BX9:[(R)-(4-fluorophenyl)-[[(2S)-2-methyl-3-sulfanyl-propanoyl]amino]methyl]boronic+acid'>BX9</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=ACY:ACETIC+ACID'>ACY</scene>, <scene name='pdbligand=BX9:[(R)-(4-fluorophenyl)-[[(2S)-2-methyl-3-sulfanyl-propanoyl]amino]methyl]boronic+acid'>BX9</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">KPC-2 ([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=6jn4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6jn4 OCA], [http://pdbe.org/6jn4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6jn4 RCSB], [http://www.ebi.ac.uk/pdbsum/6jn4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6jn4 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=6jn4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6jn4 OCA], [http://pdbe.org/6jn4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6jn4 RCSB], [http://www.ebi.ac.uk/pdbsum/6jn4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6jn4 ProSAT]</span></td></tr> | ||
Revision as of 09:35, 21 August 2019
Serine Beta-Lactamase KPC-2 in Complex with Dual MBL/SBL Inhibitor WL-001Serine Beta-Lactamase KPC-2 in Complex with Dual MBL/SBL Inhibitor WL-001
Structural highlights
Publication Abstract from PubMedThe emergence and spread of bacterial pathogens acquired both metallo-beta-lactamase (MBL) and serine-beta-lactamase (SBL) medicated beta-lactam resistance gives rise to an urgent need for the development of new dual-action MBL/SBL inhibitors. Application of a pharmacophore fusion strategy led to the identification of (2'S)-(1-(3'-mercapto-2'-methylpropanamido)methyl)boronic acid (MS01) as a new dual-action inhibitor, which manifests broad-spectrum inhibition to representative MBL/SBL enzymes, including the widespread VIM-2 and KPC-2. Guided by the VIM-2:MS01 and KPC-2:MS01 complex structures, further structural optimization yielded new more potent dual-action inhibitors. Selectivity studies indicated that the inhibitors had no apparent inhibition to human angiotensin-converting enzyme-2, and showed selectivity across serine hydrolyases in E. coli and human HEK293T cells labeled by the activity-based probe TAMRA-FP. Moreover, the inhibitors displayed potentiation of meropenem efficacy against MBL- or SBL-positive clinical isolates without apparent cytotoxicity. This work will aid efforts to develop new types of clinically useful dual-action inhibitors targeting MBL/SBL enzymes. Structure-Based Development of (1-(3'-Mercaptopropanamido)methyl)boronic Acid Derived Broad-Spectrum, Dual-Action Inhibitors of Metallo- and Serine-beta-Lactamases.,Wang YL, Liu S, Yu ZJ, Lei Y, Huang MY, Yan YH, Ma Q, Zheng Y, Deng H, Sun Y, Wu C, Yu Y, Chen Q, Wang Z, Wu Y, Li GB J Med Chem. 2019 Jul 3. doi: 10.1021/acs.jmedchem.9b00735. PMID:31269398[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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