1PW1

Non-Covalent Complex Of Streptomyces R61 DD-Peptidase With A Highly Specific Penicillin


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.20 Å
  • R-Value Free: 0.151 
  • R-Value Work: 0.116 
  • R-Value Observed: 0.116 

Starting Model: experimental
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This is version 1.4 of the entry. See complete history


Literature

Crystal structures of complexes between the R61 DD-peptidase and peptidoglycan-mimetic beta-lactams: a non-covalent complex with a "perfect penicillin"

Silvaggi, N.R.Josephine, H.R.Kuzin, A.P.Nagarajan, R.Pratt, R.F.Kelly, J.A.

(2005) J Mol Biol 345: 521-533

  • DOI: https://doi.org/10.1016/j.jmb.2004.10.076
  • Primary Citation of Related Structures:  
    1PW1, 1PW8, 1PWC, 1PWD, 1PWG

  • 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.


  • Organizational Affiliation

    Department of Molecular and Cell Biology and Institute for Materials Science, University of Connecticut, Storrs, CT 06269-3125, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
D-alanyl-D-alanine carboxypeptidase349Streptomyces sp. R61Mutation(s): 0 
EC: 3.4.16.4
UniProt
Find proteins for P15555 (Streptomyces sp. (strain R61))
Explore P15555 
Go to UniProtKB:  P15555
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP15555
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.20 Å
  • R-Value Free: 0.151 
  • R-Value Work: 0.116 
  • R-Value Observed: 0.116 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 51α = 90
b = 67β = 90
c = 100.7γ = 90
Software Package:
Software NamePurpose
SHELXL-97refinement
SCALEPACKdata scaling
CNSrefinement
DENZOdata reduction
CNSphasing

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2004-07-13
    Type: Initial release
  • Version 1.1: 2008-04-29
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Source and taxonomy, Version format compliance
  • Version 1.3: 2019-07-24
    Changes: Data collection, Derived calculations, Refinement description
  • Version 1.4: 2023-08-16
    Changes: Data collection, Database references, Derived calculations, Refinement description