PDBsum entry 2j87

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protein ligands metals Protein-protein interface(s) links
Transferase PDB id
Jmol PyMol
Protein chains
158 a.a. *
165 a.a. *
TTP ×4
_MG ×4
_ZN ×4
* Residue conservation analysis
PDB id:
Name: Transferase
Title: Structure of vaccinia virus thymidine kinase in complex with dttp: insights for drug design
Structure: Thymidine kinase. Chain: a, b, c, d. Synonym: vaccinia virus thymidine kinase. Engineered: yes
Source: Vaccinia virus. Organism_taxid: 10245. Expressed in: escherichia coli. Expression_system_taxid: 562
Biol. unit: Tetramer (from PDB file)
3.10Å     R-factor:   0.258     R-free:   0.289
Authors: K.El Omari,N.Solaroli,A.Karlsson,J.Balzarini,D.K.Stammers
Key ref: K.El Omari et al. (2006). Structure of vaccinia virus thymidine kinase in complex with dTTP: insights for drug design. BMC Struct Biol, 6, 22. PubMed id: 17062140
23-Oct-06     Release date:   13-Nov-06    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
O57203  (KITH_VACCA) -  Thymidine kinase
177 a.a.
158 a.a.*
Protein chains
Pfam   ArchSchema ?
O57203  (KITH_VACCA) -  Thymidine kinase
177 a.a.
165 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 6 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: Chains A, B, C, D: E.C.  - Thymidine kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + thymidine = ADP + thymidine 5'-phosphate
Bound ligand (Het Group name = TTP)
matches with 76.47% similarity
+ thymidine
+ thymidine 5'-phosphate
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     DNA biosynthetic process   3 terms 
  Biochemical function     nucleotide binding     6 terms  


BMC Struct Biol 6:22 (2006)
PubMed id: 17062140  
Structure of vaccinia virus thymidine kinase in complex with dTTP: insights for drug design.
K.El Omari, N.Solaroli, A.Karlsson, J.Balzarini, D.K.Stammers.
BACKGROUND: Development of countermeasures to bioterrorist threats such as those posed by the smallpox virus (variola), include vaccination and drug development. Selective activation of nucleoside analogues by virus-encoded thymidine (dThd) kinases (TK) represents one of the most successful strategies for antiviral chemotherapy as demonstrated for anti-herpes drugs. Vaccinia virus TK is a close orthologue of variola TK but also shares a relatively high sequence identity to human type 2 TK (hTK), thus achieving drug selectivity relative to the host enzyme is challenging. RESULTS: In order to identify any differences compared to hTK that may be exploitable in drug design, we have determined the crystal structure of VVTK, in complex with thymidine 5'-triphosphate (dTTP). Although most of the active site residues are conserved between hTK and VVTK, we observe a difference in conformation of residues Asp-43 and Arg-45. The equivalent residues in hTK hydrogen bond to dTTP, whereas in subunit D of VVTK, Asp-43 and Arg-45 adopt a different conformation preventing interaction with this nucleotide. Asp-43 and Arg-45 are present in a flexible loop, which is disordered in subunits A, B and C. The observed difference in conformation and flexibility may also explain the ability of VVTK to phosphorylate (South)-methanocarbathymine whereas, in contrast, no substrate activity with hTK is reported for this compound. CONCLUSION: The difference in conformation for Asp-43 and Arg-45 could thus be used in drug design to generate VVTK/Variola TK-selective nucleoside analogue substrates and/or inhibitors that have lower affinity for hTK.

Literature references that cite this PDB file's key reference

  PubMed id Reference
19946139 K.Van Vliet, M.R.Mohamed, L.Zhang, N.Y.Villa, S.J.Werden, J.Liu, and G.McFadden (2009).
Poxvirus proteomics and virus-host protein interactions.
  Microbiol Mol Biol Rev, 73, 730-749.  
18971333 C.Caillat, D.Topalis, L.A.Agrofoglio, S.Pochet, J.Balzarini, D.Deville-Bonne, and P.Meyer (2008).
Crystal structure of poxvirus thymidylate kinase: an unexpected dimerization has implications for antiviral therapy.
  Proc Natl Acad Sci U S A, 105, 16900-16905.
PDB codes: 2v54 2w0s
17325220 M.N.Prichard, K.A.Keith, M.P.Johnson, E.A.Harden, A.McBrayer, M.Luo, S.Qiu, D.Chattopadhyay, X.Fan, P.F.Torrence, and E.R.Kern (2007).
Selective phosphorylation of antiviral drugs by vaccinia virus thymidine kinase.
  Antimicrob Agents Chemother, 51, 1795-1803.  
17288553 U.Kosinska, C.Carnrot, M.P.Sandrini, A.R.Clausen, L.Wang, J.Piskur, S.Eriksson, and H.Eklund (2007).
Structural studies of thymidine kinases from Bacillus anthracis and Bacillus cereus provide insights into quaternary structure and conformational changes upon substrate binding.
  FEBS J, 274, 727-737.
PDB codes: 2j9r 2ja1
18049729 W.Tjarks, R.Tiwari, Y.Byun, S.Narayanasamy, and R.F.Barth (2007).
Carboranyl thymidine analogues for neutron capture therapy.
  Chem Commun (Camb), (), 4978-4991.  
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