4de0: Difference between revisions
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[[ | ==CTX-M-9 class A beta-lactamase complexed with compound 16== | ||
<StructureSection load='4de0' size='340' side='right' caption='[[4de0]], [[Resolution|resolution]] 1.12Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4de0]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4DE0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4DE0 FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0JB:N-[3-(1H-TETRAZOL-5-YL)PHENYL]-1H-BENZIMIDAZOLE-7-CARBOXAMIDE'>0JB</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene></td></tr> | |||
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PCA:PYROGLUTAMIC+ACID'>PCA</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3g2y|3g2y]], [[3g2z|3g2z]], [[3g30|3g30]], [[3g31|3g31]], [[3g32|3g32]], [[3g35|3g35]], [[4dds|4dds]], [[4ddy|4ddy]], [[4de1|4de1]], [[4de3|4de3]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">blaCTX-M-9, blaCTX-M-9a, blaCTX-M-9b, CTX-M ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=562 Escherichia coli])</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=4de0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4de0 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4de0 RCSB], [http://www.ebi.ac.uk/pdbsum/4de0 PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The emergence of CTX-M class A extended-spectrum beta-lactamases poses a serious health threat to the public. We have applied structure-based design to improve the potency of a novel noncovalent tetrazole-containing CTX-M inhibitor (K(i) = 21 muM) more than 200-fold via structural modifications targeting two binding hot spots, a hydrophobic shelf formed by Pro167 and a polar site anchored by Asp240. Functional groups contacting each binding hot spot independently in initial designs were later combined to produce analogues with submicromolar potencies, including 6-trifluoromethyl-3H-benzoimidazole-4-carboxylic acid [3-(1H-tetrazol-5-yl)-phenyl]-amide, which had a K(i) value of 89 nM and reduced the MIC of cefotaxime by 64-fold in CTX-M-9 expressing Escherichia coli . The in vitro potency gains were accompanied by improvements in ligand efficiency (from 0.30 to 0.39) and LipE (from 1.37 to 3.86). These new analogues represent the first nM-affinity noncovalent inhibitors of a class A beta-lactamase. Their complex crystal structures provide valuable information about ligand binding for future inhibitor design. | |||
Structure-Based Design of Potent and Ligand-Efficient Inhibitors of CTX-M Class A beta-Lactamase.,Nichols DA, Jaishankar P, Larson W, Smith E, Liu G, Beyrouthy R, Bonnet R, Renslo AR, Chen Y J Med Chem. 2012 Mar 8;55(5):2163-72. Epub 2012 Feb 14. PMID:22296601<ref>PMID:22296601</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
==See Also== | ==See Also== | ||
*[[Beta-lactamase|Beta-lactamase]] | *[[Beta-lactamase|Beta-lactamase]] | ||
== References == | |||
== | <references/> | ||
< | __TOC__ | ||
</StructureSection> | |||
[[Category: Beta-lactamase]] | [[Category: Beta-lactamase]] | ||
[[Category: Escherichia coli]] | [[Category: Escherichia coli]] | ||
[[Category: Chen, Y | [[Category: Chen, Y]] | ||
[[Category: Nichols, D N | [[Category: Nichols, D N]] | ||
[[Category: Ctx-m]] | [[Category: Ctx-m]] | ||
[[Category: Fragment]] | [[Category: Fragment]] | ||
Revision as of 19:28, 9 December 2014
CTX-M-9 class A beta-lactamase complexed with compound 16CTX-M-9 class A beta-lactamase complexed with compound 16
Structural highlights
Publication Abstract from PubMedThe emergence of CTX-M class A extended-spectrum beta-lactamases poses a serious health threat to the public. We have applied structure-based design to improve the potency of a novel noncovalent tetrazole-containing CTX-M inhibitor (K(i) = 21 muM) more than 200-fold via structural modifications targeting two binding hot spots, a hydrophobic shelf formed by Pro167 and a polar site anchored by Asp240. Functional groups contacting each binding hot spot independently in initial designs were later combined to produce analogues with submicromolar potencies, including 6-trifluoromethyl-3H-benzoimidazole-4-carboxylic acid [3-(1H-tetrazol-5-yl)-phenyl]-amide, which had a K(i) value of 89 nM and reduced the MIC of cefotaxime by 64-fold in CTX-M-9 expressing Escherichia coli . The in vitro potency gains were accompanied by improvements in ligand efficiency (from 0.30 to 0.39) and LipE (from 1.37 to 3.86). These new analogues represent the first nM-affinity noncovalent inhibitors of a class A beta-lactamase. Their complex crystal structures provide valuable information about ligand binding for future inhibitor design. Structure-Based Design of Potent and Ligand-Efficient Inhibitors of CTX-M Class A beta-Lactamase.,Nichols DA, Jaishankar P, Larson W, Smith E, Liu G, Beyrouthy R, Bonnet R, Renslo AR, Chen Y J Med Chem. 2012 Mar 8;55(5):2163-72. Epub 2012 Feb 14. PMID:22296601[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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