3opl: Difference between revisions
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[[ | ==ESBL R164H mutant SHV-1 beta-lactamase== | ||
<StructureSection load='3opl' size='340' side='right' caption='[[3opl]], [[Resolution|resolution]] 1.80Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3opl]] 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=3OPL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3OPL FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</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">[[1shv|1shv]], [[2h5s|2h5s]], [[3oph|3oph]], [[3opp|3opp]], [[3opr|3opr]]</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=3opl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3opl OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3opl RCSB], [http://www.ebi.ac.uk/pdbsum/3opl PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Among Gram-negative bacteria, resistance to beta-lactams is mediated primarily by beta-lactamases (EC 3.2.6.5), periplasmic enzymes that inactivate beta-lactam antibiotics. Substitutions at critical amino acid positions in the class A beta-lactamase families result in enzymes that can hydrolyze extended-spectrum cephalosporins, thus demonstrating an "extended-spectrum" beta-lactamase (ESBL) phenotype. Using SHV ESBLs with substitutions in the Omega loop (R164H and R164S) as target enzymes to understand this enhanced biochemical capability and to serve as a basis for novel beta-lactamase inhibitor development, we determined the spectra of activity and crystal structures of these variants. We also studied the inactivation of the R164H and R164S mutants with tazobactam and SA2-13, a unique beta-lactamase inhibitor that undergoes a distinctive reaction chemistry in the active site. We noted that the reduced Ki values for the R164H and R164S mutants with SA2-13 are comparable to those with tazobactam (submicromolar). The apo enzyme crystal structures of the R164H and R164S SHV variants revealed an ordered Omega loop architecture that became disordered when SA2-13 was bound. Important structural alterations that result from the binding of SA2-13 explain the enhanced susceptibility of these ESBL enzymes to this inhibitor and highlight ligand-dependent Omega loop flexibility as a mechanism for accommodating and hydrolyzing beta-lactam substrates. | |||
Ligand-dependent disorder of the Omega loop observed in extended-spectrum SHV-type beta-lactamase.,Sampson JM, Ke W, Bethel CR, Pagadala SR, Nottingham MD, Bonomo RA, Buynak JD, van den Akker F Antimicrob Agents Chemother. 2011 May;55(5):2303-9. Epub 2011 Feb 28. PMID:21357298<ref>PMID:21357298</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: Sampson, J M | [[Category: Sampson, J M]] | ||
[[Category: Class a beta-lactamase]] | [[Category: Class a beta-lactamase]] | ||
[[Category: Hydrolase]] | [[Category: Hydrolase]] | ||
Revision as of 14:01, 9 December 2014
ESBL R164H mutant SHV-1 beta-lactamaseESBL R164H mutant SHV-1 beta-lactamase
Structural highlights
Publication Abstract from PubMedAmong Gram-negative bacteria, resistance to beta-lactams is mediated primarily by beta-lactamases (EC 3.2.6.5), periplasmic enzymes that inactivate beta-lactam antibiotics. Substitutions at critical amino acid positions in the class A beta-lactamase families result in enzymes that can hydrolyze extended-spectrum cephalosporins, thus demonstrating an "extended-spectrum" beta-lactamase (ESBL) phenotype. Using SHV ESBLs with substitutions in the Omega loop (R164H and R164S) as target enzymes to understand this enhanced biochemical capability and to serve as a basis for novel beta-lactamase inhibitor development, we determined the spectra of activity and crystal structures of these variants. We also studied the inactivation of the R164H and R164S mutants with tazobactam and SA2-13, a unique beta-lactamase inhibitor that undergoes a distinctive reaction chemistry in the active site. We noted that the reduced Ki values for the R164H and R164S mutants with SA2-13 are comparable to those with tazobactam (submicromolar). The apo enzyme crystal structures of the R164H and R164S SHV variants revealed an ordered Omega loop architecture that became disordered when SA2-13 was bound. Important structural alterations that result from the binding of SA2-13 explain the enhanced susceptibility of these ESBL enzymes to this inhibitor and highlight ligand-dependent Omega loop flexibility as a mechanism for accommodating and hydrolyzing beta-lactam substrates. Ligand-dependent disorder of the Omega loop observed in extended-spectrum SHV-type beta-lactamase.,Sampson JM, Ke W, Bethel CR, Pagadala SR, Nottingham MD, Bonomo RA, Buynak JD, van den Akker F Antimicrob Agents Chemother. 2011 May;55(5):2303-9. Epub 2011 Feb 28. PMID:21357298[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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