1pwc
From Proteopedia
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penicilloyl acyl enzyme complex of the Streptomyces R61 DD-peptidase with penicillin G
Overview
The bacterial D-alanyl-D-alanine transpeptidases (DD-peptidases) are the, killing targets of beta-lactams, the most important clinical defense, against bacterial infections. However, due to the constant development of, antibiotic-resistance mechanisms by bacteria, there is an ever-present, need for new, more effective antimicrobial drugs. While enormous numbers, of beta-lactam compounds have been tested for antibiotic activity in over, 50 years of research, the success of a beta-lactam structure in terms of, antibiotic activity remains unpredictable. Tipper and Strominger suggested, long ago that beta-lactams inhibit DD-peptidases because they mimic the, D-alanyl-D-alanine motif of the peptidoglycan substrate of these enzymes., They also predicted that beta-lactams having a peptidoglycan-mimetic, side-chain might be better antibiotics than their non-specific, counterparts, but decades of research have not provided any evidence for, this. We have recently described two such novel beta-lactams. The first is, a penicillin having the glycyl-L-alpha-amino-epsilon-pimelyl side-chain of, Streptomyces strain R61 peptidoglycan, making it the "perfect penicillin", for this organism. The other is a cephalosporin with the same side-chain., Here, we describe the X-ray crystal structures of the perfect penicillin, in non-covalent and covalent complexes with the Streptomyces R61, DD-peptidase. The structure of the non-covalent enzyme-inhibitor complex, is the first such complex to be trapped crystallographically with a, DD-peptidase. In addition, the covalent complex of the, peptidyl-cephalosporin with the R61 DD-peptidase is described. Finally, two covalent complexes with the traditional beta-lactams benzylpenicillin, and cephalosporin C were determined for comparison with the peptidyl, beta-lactams. These structures, together with relevant kinetics data, support Tipper and Strominger's assertion that peptidoglycan-mimetic, side-chains should improve beta-lactams as inhibitors of DD-peptidases.
About this Structure
1PWC is a Single protein structure of sequence from Streptomyces sp. with PNM as ligand. Active as Serine-type D-Ala-D-Ala carboxypeptidase, with EC number 3.4.16.4 Full crystallographic information is available from OCA.
Reference
Crystal structures of complexes between the R61 DD-peptidase and peptidoglycan-mimetic beta-lactams: a non-covalent complex with a "perfect penicillin"., Silvaggi NR, Josephine HR, Kuzin AP, Nagarajan R, Pratt RF, Kelly JA, J Mol Biol. 2005 Jan 21;345(3):521-33. PMID:15581896
Page seeded by OCA on Wed Nov 21 00:10:48 2007
