1PWD

Covalent acyl enzyme complex of the Streptomyces R61 DD-peptidase with cephalosporin C

Summary for 1PWD

• Entry DOI: 10.2210/pdb1pwd/pdb
• Related: 1IKG 1IKI 1MPL
• Descriptor: D-alanyl-D-alanine carboxypeptidase precursor, (2R)-5-(acetyloxymethyl)-2-[(1R)-1-[[(5R)-5-azanyl-6-oxidanyl-6-oxidanylidene-hexanoyl]amino]-2-oxidanylidene-ethyl]-5,6-dihydro-2H-1,3-thiazine-4-carboxylic acid (3 entities in total)
• Functional Keywords: beta-lactam, antibiotics, penicillin binding protein, enzyme, peptidoglycan, hydrolase, hydrolase-antibiotic complex, hydrolase/antibiotic
• Biological source: Streptomyces sp.
• Total number of polymer chains: 1
• Total formula weight: 37840.01

Authors

Silvaggi, N.R.,Josephine, H.R.,Pratt, R.F.,Kelly, J.A. (deposition date: 2003-07-01, release date: 2004-07-13, Last modification date: 2024-10-30)

Primary citation

Silvaggi, N.R.,Josephine, H.R.,Kuzin, A.P.,Nagarajan, R.,Pratt, R.F.,Kelly, J.A.
Crystal structures of complexes between the R61 DD-peptidase and peptidoglycan-mimetic beta-lactams: a non-covalent complex with a "perfect penicillin"
J.Mol.Biol., 345:521-533, 2005

PubMed Abstract: 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.

PubMed: 15581896
DOI: 10.1016/j.jmb.2004.10.076

Experimental method

X-RAY DIFFRACTION (1.2 Å)