1o07
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Crystal Structure of the complex between Q120L/Y150E mutant of AmpC and a beta-lactam inhibitor (MXG)
OverviewOverview
Penicillin-binding proteins (PBPs), biosynthetic enzymes of bacterial cell, wall assembly, and beta-lactamases, resistance enzymes to beta-lactam, antibiotics, are related to each other from an evolutionary point of view., Massova and Mobashery (Antimicrob. Agents Chemother. 1998, 42, 1-17) have, proposed that for beta-lactamases to have become effective at their, function as antibiotic resistance enzymes, they would have had to undergo, structure alterations such that they would not interact with the, peptidoglycan, which is the substrate for PBPs. A cephalosporin analogue, 7beta-[N-Acetyl-L-alanyl-gamma-D-glutamyl-L-lysine]-3-acetoxymethyl-3-ceph, em-carboxylic acid (compound 6), was conceived and synthesized to test, this notion. The X-ray structure of the complex of this cephalosporin, bound to the active site of the deacylation-deficient Q120L/Y150E variant, of the class C AmpC beta-lactamase from Escherichia coli was solved at, 1.71 A resolution. This complex revealed that the surface for interaction, with the strand of peptidoglycan that acylates the active site, which is, present in PBPs, is absent in the -lactamase active site. Furthermore, insertion of a peptide in the beta-lactamase active site at a location, where the second strand of peptidoglycan in some PBPs binds has, effectively abolished the possibility for such interaction with the, beta-lactamase. A 2.6 ns dynamics simulation was carried out for the, complex, which revealed that the peptidoglycan surrogate (i.e., the, active-site-bound ligand) undergoes substantial motion and is not, stabilized for binding within the active site. These factors taken, together disclose the set of structure modifications in the antibiotic, resistance enzyme that prevent it from interacting with the peptidoglycan, en route to achieving catalytic proficiency for their intended function.
About this StructureAbout this Structure
1O07 is a Single protein structure of sequence from Escherichia coli with K and MXG as ligands. Active as Beta-lactamase, with EC number 3.5.2.6 Full crystallographic information is available from OCA.
ReferenceReference
Structural aspects for evolution of beta-lactamases from penicillin-binding proteins., Meroueh SO, Minasov G, Lee W, Shoichet BK, Mobashery S, J Am Chem Soc. 2003 Aug 13;125(32):9612-8. PMID:12904027
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