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==Structure of cefotaxime-CDD-1 beta-lactamase complex== | |||
<StructureSection load='6pqc' size='340' side='right'caption='[[6pqc]], [[Resolution|resolution]] 2.10Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6pqc]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6PQC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6PQC FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CEF:CEFOTAXIME,+C3+CLEAVED,+OPEN,+BOUND+FORM'>CEF</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6edm|6edm]]</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=6pqc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6pqc OCA], [http://pdbe.org/6pqc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6pqc RCSB], [http://www.ebi.ac.uk/pdbsum/6pqc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6pqc ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Class D beta-lactamases, enzymes that degrade beta-lactam antibiotics and are widely spread in Gram-negative bacteria, were for a long time not known in Gram-positive organisms. Recently, these enzymes were identified in various non-pathogenic Bacillus species and subsequently in Clostridioides difficile, a major clinical pathogen associated with high morbidity and mortality rates. Comparison of the BPU-1 enzyme from Bacillus pumilus with the CDD-1 and CDD-2 enzymes from C. difficile demonstrated that the latter enzymes have broadened their substrate profile to efficiently hydrolyze the expanded-spectrum methoxyimino cephalosporins, cefotaxime and ceftriaxone. These two antibiotics are major contributors to the development of C. difficile infection, as they suppress sensitive bacterial microflora in the gut but fail to kill the pathogen which is highly resistant to these drugs. To gain insight into the structural features that contribute to the expansion of the substrate profile of CDD enzymes compared to BPU-1, we solved the crystal structures of CDD-1 and its complex with cefotaxime. Comparison of CDD-1 structures with those of class D enzymes from Gram-negative bacteria showed that in the cefotaxime-CDD-1 complex, the antibiotic is bound in a substantially different mode due to structural differences in the enzymes' active sites. We also found that CDD-1 has a uniquely long Omega-loop when compared to all other class D beta-lactamases. This Omega-loop extension allows it to engage in hydrogen bonding with the acylated cefotaxime, thus providing additional stabilizing interactions with the substrate which could be responsible for the high catalytic activity of the enzyme for expanded-spectrum cephalosporins. | |||
The crystal structures of CDD-1, the intrinsic class D beta-lactamase from the pathogenic Gram-positive bacterium Clostridioides difficile, and its complex with cefotaxime.,Stewart NK, Smith CA, Toth M, Stasyuk A, Vakulenko SB J Struct Biol. 2019 Sep 21. pii: S1047-8477(19)30202-3. doi:, 10.1016/j.jsb.2019.09.008. PMID:31550535<ref>PMID:31550535</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Vakulenko, S | <div class="pdbe-citations 6pqc" style="background-color:#fffaf0;"></div> | ||
[[Category: | == References == | ||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Beta-lactamase]] | |||
[[Category: Large Structures]] | |||
[[Category: Smith, C A]] | |||
[[Category: Vakulenko, S B]] | |||
[[Category: Cefotaxime]] | |||
[[Category: Class d]] | |||
[[Category: Gram-positive]] | |||
[[Category: Hydrolase]] | |||
[[Category: Hydrolase-hydrolase inhibitor complex]] | |||
Revision as of 08:22, 10 October 2019
Structure of cefotaxime-CDD-1 beta-lactamase complexStructure of cefotaxime-CDD-1 beta-lactamase complex
Structural highlights
Publication Abstract from PubMedClass D beta-lactamases, enzymes that degrade beta-lactam antibiotics and are widely spread in Gram-negative bacteria, were for a long time not known in Gram-positive organisms. Recently, these enzymes were identified in various non-pathogenic Bacillus species and subsequently in Clostridioides difficile, a major clinical pathogen associated with high morbidity and mortality rates. Comparison of the BPU-1 enzyme from Bacillus pumilus with the CDD-1 and CDD-2 enzymes from C. difficile demonstrated that the latter enzymes have broadened their substrate profile to efficiently hydrolyze the expanded-spectrum methoxyimino cephalosporins, cefotaxime and ceftriaxone. These two antibiotics are major contributors to the development of C. difficile infection, as they suppress sensitive bacterial microflora in the gut but fail to kill the pathogen which is highly resistant to these drugs. To gain insight into the structural features that contribute to the expansion of the substrate profile of CDD enzymes compared to BPU-1, we solved the crystal structures of CDD-1 and its complex with cefotaxime. Comparison of CDD-1 structures with those of class D enzymes from Gram-negative bacteria showed that in the cefotaxime-CDD-1 complex, the antibiotic is bound in a substantially different mode due to structural differences in the enzymes' active sites. We also found that CDD-1 has a uniquely long Omega-loop when compared to all other class D beta-lactamases. This Omega-loop extension allows it to engage in hydrogen bonding with the acylated cefotaxime, thus providing additional stabilizing interactions with the substrate which could be responsible for the high catalytic activity of the enzyme for expanded-spectrum cephalosporins. The crystal structures of CDD-1, the intrinsic class D beta-lactamase from the pathogenic Gram-positive bacterium Clostridioides difficile, and its complex with cefotaxime.,Stewart NK, Smith CA, Toth M, Stasyuk A, Vakulenko SB J Struct Biol. 2019 Sep 21. pii: S1047-8477(19)30202-3. doi:, 10.1016/j.jsb.2019.09.008. PMID:31550535[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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