3mzd: Difference between revisions
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[[ | ==Structure of penicillin-binding protein 5 from E. coli: cloxacillin acyl-enzyme complex== | ||
<StructureSection load='3mzd' size='340' side='right' caption='[[3mzd]], [[Resolution|resolution]] 1.90Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3mzd]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3MZD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3MZD FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CXV:(2R,4S)-2-[(1S)-1-({[3-(2-CHLOROPHENYL)-5-METHYL-1,2-OXAZOL-4-YL]CARBONYL}AMINO)-2-OXOETHYL]-5,5-DIMETHYL-1,3-THIAZOLIDINE-4-CARBOXYLIC+ACID'>CXV</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1nzo|1nzo]], [[1z6f|1z6f]], [[3beb|3beb]], [[3bec|3bec]], [[3mze|3mze]], [[3mzf|3mzf]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">b0632, dacA, JW0627, pfv ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=562 Escherichia coli])</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=3mzd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3mzd OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3mzd RCSB], [http://www.ebi.ac.uk/pdbsum/3mzd PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Penicillin-binding proteins (PBPs) are the molecular targets for the widely used beta-lactam class of antibiotics, but how these compounds act at the molecular level is not fully understood. We have determined crystal structures of Escherichia coli PBP 5 as covalent complexes with imipenem, cloxacillin, and cefoxitin. These antibiotics exhibit very different second-order rates of acylation for the enzyme. In all three structures, there is excellent electron density for the central portion of the beta-lactam, but weak or absent density for the R1 or R2 side chains. Areas of contact between the antibiotics and PBP 5 do not correlate with the rates of acylation. The same is true for conformational changes, because although a shift of a loop leading to an electrostatic interaction between Arg248 and the beta-lactam carboxylate, which occurs completely with cefoxitin and partially with imipenem and is absent with cloxacillin, is consistent with the different rates of acylation, mutagenesis of Arg248 decreased the level of cefoxitin acylation only 2-fold. Together, these data suggest that structures of postcovalent complexes of PBP 5 are unlikely to be useful vehicles for the design of new covalent inhibitors of PBPs. Finally, superimposition of the imipenem-acylated complex with PBP 5 in complex with a boronic acid peptidomimetic shows that the position corresponding to the hydrolytic water molecule is occluded by the ring nitrogen of the beta-lactam. Because the ring nitrogen occupies a similar position in all three complexes, this supports the hypothesis that deacylation is blocked by the continued presence of the leaving group after opening of the beta-lactam ring. | |||
Crystal structures of covalent complexes of beta-lactam antibiotics with Escherichia coli penicillin-binding protein 5: toward an understanding of antibiotic specificity.,Nicola G, Tomberg J, Pratt RF, Nicholas RA, Davies C Biochemistry. 2010 Sep 21;49(37):8094-104. PMID:20726582<ref>PMID:20726582</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
==See Also== | ==See Also== | ||
*[[Penicillin-binding protein|Penicillin-binding protein]] | *[[Penicillin-binding protein|Penicillin-binding protein]] | ||
== References == | |||
== | <references/> | ||
< | __TOC__ | ||
</StructureSection> | |||
[[Category: Escherichia coli]] | [[Category: Escherichia coli]] | ||
[[Category: Davies, C | [[Category: Davies, C]] | ||
[[Category: Nicholas, R A | [[Category: Nicholas, R A]] | ||
[[Category: Nicola, G | [[Category: Nicola, G]] | ||
[[Category: Pratt, R F | [[Category: Pratt, R F]] | ||
[[Category: Tomberg, J | [[Category: Tomberg, J]] | ||
[[Category: Beta-lactam antibiotic]] | [[Category: Beta-lactam antibiotic]] | ||
[[Category: Dd-carboxypeptidase]] | [[Category: Dd-carboxypeptidase]] | ||
Revision as of 11:42, 9 December 2014
Structure of penicillin-binding protein 5 from E. coli: cloxacillin acyl-enzyme complexStructure of penicillin-binding protein 5 from E. coli: cloxacillin acyl-enzyme complex
Structural highlights
Publication Abstract from PubMedPenicillin-binding proteins (PBPs) are the molecular targets for the widely used beta-lactam class of antibiotics, but how these compounds act at the molecular level is not fully understood. We have determined crystal structures of Escherichia coli PBP 5 as covalent complexes with imipenem, cloxacillin, and cefoxitin. These antibiotics exhibit very different second-order rates of acylation for the enzyme. In all three structures, there is excellent electron density for the central portion of the beta-lactam, but weak or absent density for the R1 or R2 side chains. Areas of contact between the antibiotics and PBP 5 do not correlate with the rates of acylation. The same is true for conformational changes, because although a shift of a loop leading to an electrostatic interaction between Arg248 and the beta-lactam carboxylate, which occurs completely with cefoxitin and partially with imipenem and is absent with cloxacillin, is consistent with the different rates of acylation, mutagenesis of Arg248 decreased the level of cefoxitin acylation only 2-fold. Together, these data suggest that structures of postcovalent complexes of PBP 5 are unlikely to be useful vehicles for the design of new covalent inhibitors of PBPs. Finally, superimposition of the imipenem-acylated complex with PBP 5 in complex with a boronic acid peptidomimetic shows that the position corresponding to the hydrolytic water molecule is occluded by the ring nitrogen of the beta-lactam. Because the ring nitrogen occupies a similar position in all three complexes, this supports the hypothesis that deacylation is blocked by the continued presence of the leaving group after opening of the beta-lactam ring. Crystal structures of covalent complexes of beta-lactam antibiotics with Escherichia coli penicillin-binding protein 5: toward an understanding of antibiotic specificity.,Nicola G, Tomberg J, Pratt RF, Nicholas RA, Davies C Biochemistry. 2010 Sep 21;49(37):8094-104. PMID:20726582[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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