6d1k: Difference between revisions
No edit summary |
No edit summary |
||
| Line 3: | Line 3: | ||
<StructureSection load='6d1k' size='340' side='right'caption='[[6d1k]], [[Resolution|resolution]] 1.20Å' scene=''> | <StructureSection load='6d1k' size='340' side='right'caption='[[6d1k]], [[Resolution|resolution]] 1.20Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6d1k]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6D1K OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6D1K FirstGlance]. <br> | <table><tr><td colspan='2'>[[6d1k]] is a 1 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=6D1K OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6D1K 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=M3Q:[(quinolin-8-yl)methyl]phosphonic+acid'>M3Q</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=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=M3Q:[(quinolin-8-yl)methyl]phosphonic+acid'>M3Q</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">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=6d1k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6d1k OCA], [http://pdbe.org/6d1k PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6d1k RCSB], [http://www.ebi.ac.uk/pdbsum/6d1k PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6d1k 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=6d1k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6d1k OCA], [http://pdbe.org/6d1k PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6d1k RCSB], [http://www.ebi.ac.uk/pdbsum/6d1k PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6d1k ProSAT]</span></td></tr> | ||
| Line 10: | Line 11: | ||
== Function == | == Function == | ||
[[http://www.uniprot.org/uniprot/BLAN1_KLEPN BLAN1_KLEPN]] Confers resistance to many beta-lactam antibiotics, including some carbapenems. Does not confer resistance to the polymixin colistin or the fluoroquinolone ciprofloxacin. | [[http://www.uniprot.org/uniprot/BLAN1_KLEPN BLAN1_KLEPN]] Confers resistance to many beta-lactam antibiotics, including some carbapenems. Does not confer resistance to the polymixin colistin or the fluoroquinolone ciprofloxacin. | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Gram-negative pathogens expressing serine beta-lactamases (SBLs) and metallo-beta-lactamases (MBLs), especially those with carbapenemase activity, threaten the clinical utility of almost all beta-lactam antibiotics. Here we describe the discovery of a heteroaryl phosphonate scaffold that exhibits noncovalent cross-class inhibition of representative carbapenemases, specifically the SBL KPC-2 and the MBLs NDM-1 and VIM-2. The most potent lead, compound 16, exhibited low nM to low muM inhibition of KPC-2, NDM-1, and VIM-2. Compound 16 potentiated imipenem efficacy against resistant clinical and laboratory bacterial strains expressing carbapenemases while showing some cytotoxicity toward human HEK293T cells only at concentrations above 100 mug/mL. Complex structures with KPC-2, NDM-1, and VIM-2 demonstrate how these inhibitors achieve high binding affinity to both enzyme classes. These findings provide a structurally and mechanistically new scaffold for drug discovery targeting multidrug resistant Gram-negative pathogens and more generally highlight the active site features of carbapenemases that can be leveraged for lead discovery. | |||
Heteroaryl Phosphonates as Noncovalent Inhibitors of Both Serine- and Metallocarbapenemases.,Pemberton OA, Jaishankar P, Akhtar A, Adams JL, Shaw LN, Renslo AR, Chen Y J Med Chem. 2019 Sep 26;62(18):8480-8496. doi: 10.1021/acs.jmedchem.9b00728. Epub, 2019 Sep 13. PMID:31483651<ref>PMID:31483651</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6d1k" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||