4ddy: Difference between revisions

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-[[Image:4ddy.png|left|200px]]
+==CTX-M-9 class A beta-lactamase complexed with compound 10==
+<StructureSection load='4ddy' size='340' side='right' caption='[[4ddy]], [[Resolution|resolution]] 1.36&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[4ddy]] 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=4DDY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4DDY FirstGlance]. <br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=DN6:N-[3-(1H-TETRAZOL-5-YL)PHENYL]-3-(TRIFLUOROMETHYL)BENZAMIDE'>DN6</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]], [[4de0|4de0]], [[4de1|4de1]], [[4de2|4de2]], [[4de3|4de3]], [[4de5|4de5]]</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=4ddy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ddy OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4ddy RCSB], [http://www.ebi.ac.uk/pdbsum/4ddy 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_4ddy|  PDB=4ddy  |  SCENE=  }}
+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>
-===CTX-M-9 class A beta-lactamase complexed with compound 10===
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
-{{ABSTRACT_PUBMED_22296601}}
-==About this Structure==
-[[4ddy]] 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=4DDY OCA].
 ==See Also==
 *[[Beta-lactamase|Beta-lactamase]]
+== References ==
-==Reference==
+<references/>
-<ref group="xtra">PMID:022296601</ref><references group="xtra"/>
+__TOC__
+</StructureSection>
 [[Category: Beta-lactamase]]
 [[Category: Escherichia coli]]
-[[Category: Chen, Y.]]
+[[Category: Chen, Y]]
-[[Category: Nichols, D A.]]
+[[Category: Nichols, D A]]
 [[Category: Ctx-m]]
 [[Category: Fragment]]