2pu2: Difference between revisions
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==AmpC beta-lactamase with bound Phthalamide inhibitor== | ==AmpC beta-lactamase with bound Phthalamide inhibitor== | ||
<StructureSection load='2pu2' size='340' side='right' caption='[[2pu2]], [[Resolution|resolution]] 1.86Å' scene=''> | <StructureSection load='2pu2' size='340' side='right' caption='[[2pu2]], [[Resolution|resolution]] 1.86Å' scene=''> | ||
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ampC, ampA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=562 "Bacillus coli" Migula 1895])</td></tr> | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ampC, ampA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=562 "Bacillus coli" Migula 1895])</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=2pu2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2pu2 OCA], [http://pdbe.org/2pu2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2pu2 RCSB], [http://www.ebi.ac.uk/pdbsum/2pu2 PDBsum]</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=2pu2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2pu2 OCA], [http://pdbe.org/2pu2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2pu2 RCSB], [http://www.ebi.ac.uk/pdbsum/2pu2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2pu2 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
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</div> | </div> | ||
<div class="pdbe-citations 2pu2" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 2pu2" style="background-color:#fffaf0;"></div> | ||
== References == | == References == | ||
<references/> | <references/> | ||
Revision as of 12:32, 18 October 2017
AmpC beta-lactamase with bound Phthalamide inhibitorAmpC beta-lactamase with bound Phthalamide inhibitor
Structural highlights
Function[AMPC_ECOLI] This protein is a serine beta-lactamase with a substrate specificity for cephalosporins. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedHigh-throughput screening (HTS) is widely used in drug discovery. Especially for screens of unbiased libraries, false positives can dominate "hit lists"; their origins are much debated. Here we determine the mechanism of every active hit from a screen of 70,563 unbiased molecules against beta-lactamase using quantitative HTS (qHTS). Of the 1274 initial inhibitors, 95% were detergent-sensitive and were classified as aggregators. Among the 70 remaining were 25 potent, covalent-acting beta-lactams. Mass spectra, counter-screens, and crystallography identified 12 as promiscuous covalent inhibitors. The remaining 33 were either aggregators or irreproducible. No specific reversible inhibitors were found. We turned to molecular docking to prioritize molecules from the same library for testing at higher concentrations. Of 16 tested, 2 were modest inhibitors. Subsequent X-ray structures corresponded to the docking prediction. Analog synthesis improved affinity to 8 microM. These results suggest that it may be the physical behavior of organic molecules, not their reactivity, that accounts for most screening artifacts. Structure-based methods may prioritize weak-but-novel chemotypes in unbiased library screens. Comprehensive Mechanistic Analysis of Hits from High-Throughput and Docking Screens against beta-Lactamase.,Babaoglu K, Simeonov A, Irwin JJ, Nelson ME, Feng B, Thomas CJ, Cancian L, Costi MP, Maltby DA, Jadhav A, Inglese J, Austin CP, Shoichet BK J Med Chem. 2008 Mar 12;. PMID:18333608[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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