4fh2: Difference between revisions
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==Structure of s70c beta-lactamase bound to sulbactam== | |||
=== | <StructureSection load='4fh2' size='340' side='right' caption='[[4fh2]], [[Resolution|resolution]] 1.44Å' scene=''> | ||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4fh2]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Klebsiella_pneumoniae Klebsiella pneumoniae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4FH2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4FH2 FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0RN:SULBACTAM'>0RN</scene>, <scene name='pdbligand=MA4:CYCLOHEXYL-HEXYL-BETA-D-MALTOSIDE'>MA4</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4fd8|4fd8]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">bla, shv1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=573 Klebsiella pneumoniae])</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=4fh2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4fh2 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4fh2 RCSB], [http://www.ebi.ac.uk/pdbsum/4fh2 PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The rise of inhibitor-resistant and other beta-lactamase variants is generating an interest in developing new beta-lactamase inhibitors to complement currently available antibiotics. To gain insight into the chemistry of recognition, we determined the crystal structure of the inhibitor pre-acylation complex of sulbactam, a clinical beta-lactamase inhibitor, bound in the active site of the S70C variant of SHV-1 beta-lactamase that is normally present in Klebsiella pneumoniae. The S70C mutation was designed to affect the reactivity of that catalytic residue and to allow for capture of the pre-acylation complex. Unexpectedly, the 1.45A resolution inhibitor complex structure revealed that residue C70 is involved in a sulfenamide bond with K73. Such a covalent bond is not present in the wild type SHV-1 or in an apo S70C structure also determined in this study. This bond likely contributed significantly to obtaining the pre-acylation complex with sulbactam due to further decreased reactivity towards substrates. The intact sulbactam is positioned in the active site such that its carboxyl moiety interacts with R244, S130, and T235 and its carbonyl moiety is situated in the oxyanion hole. To our knowledge, in addition to being the first pre-acylation inhibitor beta-lactamase complex, this is also the first observation of a sulfenamide bond between a cysteine and lysine in an active site. Our results could therefore not only aid structure-based inhibitor design efforts in class A beta-lactamases, but the sulfenamide-bond forming approach to yield pre-acylation complexes could also be applied to other classes of beta-lactamases and penicillin-binding proteins with the SXXK motif. | |||
Crystal structure of a pre-acylation complex of the beta-lactamase inhibitor, sulbactam, bound to a sulfenamide bond containing thiol-beta-lactamase.,Rodkey EA, Drawz SM, Sampson JM, Bethel CR, Bonomo RA, van den Akker F J Am Chem Soc. 2012 Sep 13. PMID:22974281<ref>PMID:22974281</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
==See Also== | ==See Also== | ||
*[[Beta-lactamase|Beta-lactamase]] | *[[Beta-lactamase|Beta-lactamase]] | ||
== References == | |||
== | <references/> | ||
__TOC__ | |||
</StructureSection> | |||
[[Category: Beta-lactamase]] | [[Category: Beta-lactamase]] | ||
[[Category: Klebsiella pneumoniae]] | [[Category: Klebsiella pneumoniae]] | ||
[[Category: Akker, F van den | [[Category: Akker, F van den]] | ||
[[Category: Rodkey, E A | [[Category: Rodkey, E A]] | ||
[[Category: Class a beta-lactamase]] | [[Category: Class a beta-lactamase]] | ||
[[Category: Hydrolase]] | [[Category: Hydrolase]] | ||
[[Category: Hydrolase-hydrolase inhibitor complex]] | [[Category: Hydrolase-hydrolase inhibitor complex]] | ||
Revision as of 16:04, 4 January 2015
Structure of s70c beta-lactamase bound to sulbactamStructure of s70c beta-lactamase bound to sulbactam
Structural highlights
Publication Abstract from PubMedThe rise of inhibitor-resistant and other beta-lactamase variants is generating an interest in developing new beta-lactamase inhibitors to complement currently available antibiotics. To gain insight into the chemistry of recognition, we determined the crystal structure of the inhibitor pre-acylation complex of sulbactam, a clinical beta-lactamase inhibitor, bound in the active site of the S70C variant of SHV-1 beta-lactamase that is normally present in Klebsiella pneumoniae. The S70C mutation was designed to affect the reactivity of that catalytic residue and to allow for capture of the pre-acylation complex. Unexpectedly, the 1.45A resolution inhibitor complex structure revealed that residue C70 is involved in a sulfenamide bond with K73. Such a covalent bond is not present in the wild type SHV-1 or in an apo S70C structure also determined in this study. This bond likely contributed significantly to obtaining the pre-acylation complex with sulbactam due to further decreased reactivity towards substrates. The intact sulbactam is positioned in the active site such that its carboxyl moiety interacts with R244, S130, and T235 and its carbonyl moiety is situated in the oxyanion hole. To our knowledge, in addition to being the first pre-acylation inhibitor beta-lactamase complex, this is also the first observation of a sulfenamide bond between a cysteine and lysine in an active site. Our results could therefore not only aid structure-based inhibitor design efforts in class A beta-lactamases, but the sulfenamide-bond forming approach to yield pre-acylation complexes could also be applied to other classes of beta-lactamases and penicillin-binding proteins with the SXXK motif. Crystal structure of a pre-acylation complex of the beta-lactamase inhibitor, sulbactam, bound to a sulfenamide bond containing thiol-beta-lactamase.,Rodkey EA, Drawz SM, Sampson JM, Bethel CR, Bonomo RA, van den Akker F J Am Chem Soc. 2012 Sep 13. PMID:22974281[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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