4x69: Difference between revisions

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-'''Unreleased structure'''
+==Crystal structure of OP0595 complexed with CTX-M-44==
+<StructureSection load='4x69' size='340' side='right' caption='[[4x69]], [[Resolution|resolution]] 1.42&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[4x69]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4X69 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4X69 FirstGlance]. <br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=OP0:(2S,5R)-N-(2-AMINOETHOXY)-1-FORMYL-5-[(SULFOOXY)AMINO]PIPERIDINE-2-CARBOXAMIDE'>OP0</scene></td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4x68|4x68]]</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=4x69 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4x69 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4x69 RCSB], [http://www.ebi.ac.uk/pdbsum/4x69 PDBsum]</span></td></tr>
+</table>
+== Function ==
+[[http://www.uniprot.org/uniprot/BLT1_ECOLX BLT1_ECOLX]] Has strong cefotaxime-hydrolyzing activity.
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+OBJECTIVES: The production of a growing diversity of beta-lactamases by Gram-negative bacteria challenges antimicrobial chemotherapy. OP0595, discovered separately by each of Meiji Seika Pharma and Fedora Pharmaceuticals, is a new diazabicyclooctane serine beta-lactamase inhibitor that also acts as an antibiotic and as a beta-lactamase-independent beta-lactam 'enhancer'. METHODS: Inhibitory activity against serine beta-lactamases and affinity for PBPs were determined using nitrocefin and Bocillin FL, respectively. MICs alone and in combination with beta-lactam agents were measured according to CLSI recommendations. Morphological changes in Escherichia coli were examined by phase-contrast microscopy. RESULTS: IC50s of OP0595 for class A and C beta-lactamases were &lt;1000 nM, with covalent binding demonstrated to the active-site serine of CTX-M-44 and AmpC enzymes. OP0595 also had direct antibiotic activity against many Enterobacteriaceae, associated with inhibition of PBP2 and conversion of the bacteria into spherical forms. Synergy between OP0595 and beta-lactam agents was seen against strains producing class A and C beta-lactamases vulnerable to inhibition. Lastly, OP0595 lowered the MICs of PBP3-targeted partner beta-lactam agents for a non-beta-lactamase-producing E. coli mutant that was resistant to OP0595 itself, indicating beta-lactamase-independent 'enhancer'-based synergy. CONCLUSIONS: OP0595 acts in three ways: (i) as an inhibitor of class A and C beta-lactamases, covalently binding at their active sites; (ii) as an antibacterial, by inhibiting PBP2 of several Enterobacteriaceae; and (iii) as an 'enhancer' of beta-lactam agents that bind to other PBPs besides PBP2 for several Enterobacteriaceae. OP0595 has considerable potential to overcome resistance when it is combined with various beta-lactam agents.
-The entry 4x69 is ON HOLD  until Paper Publication
+OP0595, a new diazabicyclooctane: mode of action as a serine beta-lactamase inhibitor, antibiotic and beta-lactam 'enhancer'.,Morinaka A, Tsutsumi Y, Yamada M, Suzuki K, Watanabe T, Abe T, Furuuchi T, Inamura S, Sakamaki Y, Mitsuhashi N, Ida T, Livermore DM J Antimicrob Chemother. 2015 Jun 18. pii: dkv166. PMID:26089439<ref>PMID:26089439</ref>
-Authors: Yamada, M., Watanabe, T.
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
-Description:
+== References ==
-[[Category: Unreleased Structures]]
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Beta-lactamase]]
+[[Category: Watanabe, T]]
 [[Category: Yamada, M]]
-[[Category: Watanabe, T]]
+[[Category: Hydrolase-hydrolase inhibitor complex]]