2V54

Crystal structure of vaccinia virus thymidylate kinase bound to TDP


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.276 
  • R-Value Work: 0.216 
  • R-Value Observed: 0.216 

Starting Model: experimental
View more details

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Crystal Structure of Poxvirus Thymidylate Kinase: An Unexpected Dimerization Has Implications for Antiviral Therapy

Caillat, C.Topalis, D.Agrofoglio, L.A.Pochet, S.Balzarini, J.Deville-Bonne, D.Meyer, P.

(2008) Proc Natl Acad Sci U S A 105: 16900

  • DOI: https://doi.org/10.1073/pnas.0804525105
  • Primary Citation of Related Structures:  
    2V54, 2W0S

  • PubMed Abstract: 

    Unlike most DNA viruses, poxviruses replicate in the cytoplasm of host cells. They encode enzymes needed for genome replication and transcription, including their own thymidine and thymidylate kinases. Some herpes viruses encode only 1 enzyme catalyzing both reactions, a peculiarity used for prodrug activation to obtain maximum specificity. We have solved the crystal structures of vaccinia virus thymidylate kinase bound to TDP or brivudin monophosphate. Although the viral and human enzymes have similar sequences (42% identity), they differ in their homodimeric association and active-site geometry. The vaccinia TMP kinase dimer arrangement is orthogonal and not antiparallel as in human enzyme. This different monomer orientation is related to the presence of a canal connecting the edge of the dimer interface to the TMP base binding pocket. Consequently, the pox enzyme accommodates nucleotides with bulkier bases, like brivudin monophosphate and dGMP; these are efficiently phosphorylated and stabilize the enzyme. The brivudin monophosphate-bound structure explains the structural basis for this specificity, opening the way to the rational development of specific antipox agents that may also be suitable for poxvirus TMP kinase gene-based chemotherapy of cancer.


  • Organizational Affiliation

    Laboratoire d'Enzymologie et Biochimie Structurales, Centre National de la Recherche Scientifique, Unité Propre de Recherche 3082, 91 198 Gif-sur-Yvette Cedex, France.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
THYMIDYLATE KINASE
A, B
204Vaccinia virus CopenhagenMutation(s): 0 
EC: 2.7.4.9
UniProt
Find proteins for P68693 (Vaccinia virus (strain Copenhagen))
Explore P68693 
Go to UniProtKB:  P68693
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP68693
Sequence Annotations
Expand
  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.276 
  • R-Value Work: 0.216 
  • R-Value Observed: 0.216 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 56.77α = 90
b = 55.59β = 90
c = 161.17γ = 90
Software Package:
Software NamePurpose
CNSrefinement
XDSdata reduction
XDSdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2008-10-21
    Type: Initial release
  • Version 1.1: 2011-05-08
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2023-12-13
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description