1MR7

Crystal Structure of Streptogramin A Acetyltransferase


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.207 
  • R-Value Work: 0.176 
  • R-Value Observed: 0.178 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Structural Basis of Synercid (Quinupristin-Dalfopristin) Resistance in Gram-positive Bacterial Pathogens

Kehoe, L.E.Snidwongse, J.Courvalin, P.Rafferty, J.B.Murray, I.A.

(2003) J Biol Chem 278: 29963-29970

  • DOI: https://doi.org/10.1074/jbc.M303766200
  • Primary Citation of Related Structures:  
    1MR7, 1MR9, 1MRL

  • PubMed Abstract: 

    Synercid, a new semisynthetic streptogramin-derived antibiotic containing dalfopristin and quinupristin, is used in treatment of life-threatening infections caused by glycopeptide-resistant Enterococcus faecium and other bacterial pathogens. However, dissemination of genes encoding virginiamycin acetyltransferases, enzymes that confer resistance to streptogramins, threatens to limit the medical utility of the quinupristin-dalfopristin combination. Here we present structures of virginiamycin acetyltransferase D (VatD) determined at 1.8 A resolution in the absence of ligands, at 2.8 A resolution bound to dalfopristin, and at 3.0 A resolution in the presence of acetyl-coenzyme A. Dalfopristin is bound by VatD in a similar conformation to that described previously for the streptogramin virginiamycin M1. However, specific interactions with the substrate are altered as a consequence of a conformational change in the pyrollidine ring that is propagated to adjacent constituents of the dalfopristin macrocycle. Inactivation of dalfopristin involves acetyl transfer from acetyl-coenzyme A to the sole (O-18) hydroxy group of the antibiotic that lies close to the side chain of the strictly conserved residue, His-82. Replacement of residue 82 by alanine is accompanied by a fall in specific activity of >105-fold, indicating that the imidazole moiety of His-82 is a major determinant of catalytic rate enhancement by VatD. The structure of the VatD-dalfopristin complex can be used to predict positions where further structural modification of the drug might preclude enzyme binding and thereby circumvent Synercid resistance.


  • Organizational Affiliation

    Krebs Institute for Biomolecular Sciences, Department of Molecular Biology and Biotechnology, University of Sheffield, Western Bank, Sheffield S10 2TN, United Kingdom.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Streptogramin A Acetyltransferase209Enterococcus faeciumMutation(s): 0 
EC: 2.3.1
UniProt
Find proteins for P50870 (Enterococcus faecium)
Explore P50870 
Go to UniProtKB:  P50870
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP50870
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.207 
  • R-Value Work: 0.176 
  • R-Value Observed: 0.178 
  • Space Group: F 2 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 181.393α = 90
b = 183.001β = 90
c = 184.124γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
SHELXDphasing
REFMACrefinement

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2003-08-26
    Type: Initial release
  • Version 1.1: 2008-04-28
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Advisory, Version format compliance
  • Version 1.3: 2024-03-13
    Changes: Data collection, Database references