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==Crystal structure of serratia fonticola carbapenemase SFC-1 E166A mutant with the acylenzyme intermediate of meropenem== | |||
<StructureSection load='4ev4' size='340' side='right' caption='[[4ev4]], [[Resolution|resolution]] 1.30Å' scene=''> | |||
{ | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4ev4]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Serratia_fonticola Serratia fonticola]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4EV4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4EV4 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=MER:(4R,5S)-3-{[(3S,5S)-5-(DIMETHYLCARBAMOYL)PYRROLIDIN-3-YL]SULFANYL}-5-[(2S,3R)-3-HYDROXY-1-OXOBUTAN-2-YL]-4-METHYL-4,5-DIHYDRO-1H-PYRROLE-2-CARBOXYLIC+ACID'>MER</scene></td></tr> | |||
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=HAR:N-OMEGA-HYDROXY-L-ARGININE'>HAR</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4eqi|4eqi]], [[4euz|4euz]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BLASFC-1, SFC-1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=47917 Serratia fonticola])</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=4ev4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ev4 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4ev4 RCSB], [http://www.ebi.ac.uk/pdbsum/4ev4 PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Carbapenems are the most potent beta-lactam antibiotics and key drugs for treating infections by Gram-negative bacteria. In such organisms, beta-lactam resistance arises principally from beta-lactamase production. Although carbapenems escape the activity of most beta-lactamases, due in the class A enzymes to slow deacylation of the covalent acylenzyme intermediate, carbapenem-hydrolyzing class A beta-lactamases are now disseminating in clinically relevant bacteria. The reasons why carbapenems are substrates for these enzymes, but inhibit other class A beta-lactamases, remain to be fully established. Here, we present crystal structures of the class A carbapenemase SFC-1 from Serratia fonticola and of complexes of its Ser70 Ala (Michaelis) and Glu166 Ala (acylenzyme) mutants with the carbapenem meropenem. These are the first crystal structures of carbapenem complexes of a class A carbapenemase. Our data reveal that, in the SFC-1 acylenzyme complex, the meropenem 6alpha-1R-hydroxyethyl group interacts with Asn132, but not with the deacylating water molecule. Molecular dynamics simulations indicate that this mode of binding occurs in both the Michaelis and acylenzyme complexes of wild-type SFC-1. In carbapenem-inhibited class A beta-lactamases, it is proposed that the deacylating water molecule is deactivated by interaction with the carbapenem 6alpha-1R-hydroxyethyl substituent. Structural comparisons with such enzymes suggest that in SFC-1 subtle repositioning of key residues (Ser70, Ser130, Asn132 and Asn170) enlarges the active site, permitting rotation of the carbapenem 6alpha-1R-hydroxyethyl group and abolishing this contact. Our data show that SFC-1, and by implication other such carbapenem-hydrolyzing enzymes, uses Asn132 to orient bound carbapenems for efficient deacylation and prevent their interaction with the deacylating water molecule. | |||
The basis for carbapenem hydrolysis by class A beta-lactamases: a combined investigation using crystallography and simulations.,Fonseca F, Chudyk EI, van der Kamp MW, Correia A, Mulholland AJ, Spencer J J Am Chem Soc. 2012 Nov 7;134(44):18275-85. doi: 10.1021/ja304460j. Epub 2012 Oct, 29. PMID:23030300<ref>PMID:23030300</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: Serratia fonticola]] | [[Category: Serratia fonticola]] | ||
[[Category: Fonseca, F | [[Category: Fonseca, F]] | ||
[[Category: Spencer, J | [[Category: Spencer, J]] | ||
[[Category: Antibiotic resistance]] | [[Category: Antibiotic resistance]] | ||
[[Category: Beta-lactamase complex]] | [[Category: Beta-lactamase complex]] | ||