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[[ | ==Crystal structure of AmpC beta-lactamase in complex with a 2-trifluoromethyl-4-tetrazolyl benzene sulfonamide boronic acid inhibitor== | ||
<StructureSection load='4e3n' size='340' side='right' caption='[[4e3n]], [[Resolution|resolution]] 1.49Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4e3n]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Escherichia_coli_k-12 Escherichia coli k-12]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4E3N OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4E3N FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0NE:[({[4-(1H-TETRAZOL-5-YL)-2-(TRIFLUOROMETHYL)PHENYL]SULFONYL}AMINO)METHYL]BORONIC+ACID'>0NE</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4e3i|4e3i]], [[4e3j|4e3j]], [[4e3k|4e3k]], [[4e3l|4e3l]], [[4e3m|4e3m]], [[4e3o|4e3o]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ampA, ampC, b4150, JW4111 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=83333 Escherichia coli K-12])</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=4e3n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4e3n OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4e3n RCSB], [http://www.ebi.ac.uk/pdbsum/4e3n PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Fragment-based design was used to guide derivatization of a lead series of beta-lactamase inhibitors that had heretofore resisted optimization for in vivo activity. X-ray structures of fragments overlaid with the lead suggested new, unanticipated functionality and points of attachment. Synthesis of three derivatives improved affinity over 20-fold and improved efficacy in cell culture. Crystal structures were consistent with the fragment-based design, enabling further optimization to a K(i) of 50 pM, a 500-fold improvement that required the synthesis of only six derivatives. One of these, compound 5, was tested in mice. Whereas cefotaxime alone failed to cure mice infected with beta-lactamase-expressing Escherichia coli, 65% were cleared of infection when treated with a cefotaxime:5 combination. Fragment complexes offer a path around design hurdles, even for advanced molecules; the series described here may provide leads to overcome beta-lactamase-based resistance, a key clinical challenge. | |||
Fragment-guided design of subnanomolar beta-lactamase inhibitors active in vivo.,Eidam O, Romagnoli C, Dalmasso G, Barelier S, Caselli E, Bonnet R, Shoichet BK, Prati F Proc Natl Acad Sci U S A. 2012 Oct 23;109(43):17448-53. doi:, 10.1073/pnas.1208337109. Epub 2012 Oct 5. PMID:23043117<ref>PMID:23043117</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
==See Also== | |||
== | *[[Beta-lactamase|Beta-lactamase]] | ||
[[ | == References == | ||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Beta-lactamase]] | [[Category: Beta-lactamase]] | ||
[[Category: Escherichia coli k-12]] | [[Category: Escherichia coli k-12]] | ||
[[Category: Eidam, O | [[Category: Eidam, O]] | ||
[[Category: Shoichet, B K | [[Category: Shoichet, B K]] | ||
[[Category: Ampc beta-lactamase]] | [[Category: Ampc beta-lactamase]] | ||
[[Category: Cephalosporinase]] | [[Category: Cephalosporinase]] | ||
[[Category: Class c]] | [[Category: Class c]] | ||
[[Category: Hydrolase-hydrolase inhibitor complex]] | [[Category: Hydrolase-hydrolase inhibitor complex]] | ||
Revision as of 18:27, 9 December 2014
Crystal structure of AmpC beta-lactamase in complex with a 2-trifluoromethyl-4-tetrazolyl benzene sulfonamide boronic acid inhibitorCrystal structure of AmpC beta-lactamase in complex with a 2-trifluoromethyl-4-tetrazolyl benzene sulfonamide boronic acid inhibitor
Structural highlights
Publication Abstract from PubMedFragment-based design was used to guide derivatization of a lead series of beta-lactamase inhibitors that had heretofore resisted optimization for in vivo activity. X-ray structures of fragments overlaid with the lead suggested new, unanticipated functionality and points of attachment. Synthesis of three derivatives improved affinity over 20-fold and improved efficacy in cell culture. Crystal structures were consistent with the fragment-based design, enabling further optimization to a K(i) of 50 pM, a 500-fold improvement that required the synthesis of only six derivatives. One of these, compound 5, was tested in mice. Whereas cefotaxime alone failed to cure mice infected with beta-lactamase-expressing Escherichia coli, 65% were cleared of infection when treated with a cefotaxime:5 combination. Fragment complexes offer a path around design hurdles, even for advanced molecules; the series described here may provide leads to overcome beta-lactamase-based resistance, a key clinical challenge. Fragment-guided design of subnanomolar beta-lactamase inhibitors active in vivo.,Eidam O, Romagnoli C, Dalmasso G, Barelier S, Caselli E, Bonnet R, Shoichet BK, Prati F Proc Natl Acad Sci U S A. 2012 Oct 23;109(43):17448-53. doi:, 10.1073/pnas.1208337109. Epub 2012 Oct 5. PMID:23043117[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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