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PDBsum entry 1osn

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protein ligands Protein-protein interface(s) links
Transferase PDB id
1osn
Jmol
Contents
Protein chains
325 a.a. *
Ligands
ADP ×4
BVP ×4
Waters ×2
* Residue conservation analysis
PDB id:
1osn
Name: Transferase
Title: Crystal structure of varicella zoster virus thymidine kinase in complex with bvdu-mp and adp
Structure: Thymidine kinase. Chain: a, b, c, d. Synonym: vzv-tk. Engineered: yes
Source: Human herpesvirus 3. Varicella-zoster virus. Organism_taxid: 10335. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693.
Biol. unit: Dimer (from PQS)
Resolution:
3.20Å     R-factor:   0.235     R-free:   0.268
Authors: L.E.Bird,J.Ren,A.Wright,K.D.Leslie,B.Degreve,J.Balzarini, D.K.Stammers
Key ref:
L.E.Bird et al. (2003). Crystal structure of varicella zoster virus thymidine kinase. J Biol Chem, 278, 24680-24687. PubMed id: 12686543 DOI: 10.1074/jbc.M302025200
Date:
20-Mar-03     Release date:   10-Jun-03    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P0C0E6  (KITH_VZVO) -  Thymidine kinase
Seq:
Struc:
341 a.a.
325 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.2.7.1.21  - Thymidine kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + thymidine = ADP + thymidine 5'-phosphate
ATP
+ thymidine
= ADP
+
thymidine 5'-phosphate
Bound ligand (Het Group name = BVP)
matches with 91.00% similarity
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     phosphorylation   3 terms 
  Biochemical function     nucleotide binding     5 terms  

 

 
    reference    
 
 
DOI no: 10.1074/jbc.M302025200 J Biol Chem 278:24680-24687 (2003)
PubMed id: 12686543  
 
 
Crystal structure of varicella zoster virus thymidine kinase.
L.E.Bird, J.Ren, A.Wright, K.D.Leslie, B.Degrève, J.Balzarini, D.K.Stammers.
 
  ABSTRACT  
 
Herpes virus thymidine kinases are responsible for the activation of nucleoside antiviral drugs including (E)-5-(2-bromovinyl)-2'-deoxyuridine. Such viral thymidine kinases (tk), beside having a broader substrate specificity compared with host cell enzymes, also show significant variation in nucleoside phosphorylation among themselves. We have determined the crystal structure of Varicella zoster virus (VZV, human herpes virus 3) thymidine kinase complexed with (E)-5-(2-bromovinyl)-2'-deoxyuridine 5'-monophosphate and ADP. Differences in the conformation of a loop region (residues 55-61) and the position of two alpha-helices at the subunit interface of VZV-tk compared with the herpes simplex virus type 1 (human herpes virus 1) enzyme give rise to changes in the positioning of residues such as tyrosine 66 and glutamine 90, which hydrogen bond to the substrate in the active site. Such changes in combination with the substitution in VZV-tk of two phenylalanine residues (in place of a tyrosine and methionine), which sandwich the substrate pyrimidine ring, cause an alteration in the positioning of the base. The interaction of the (E)-5-(2-bromovinyl)-2'-deoxyuridine deoxyribose ring with the protein is altered by substitution of tyrosine 21 and phenylalanine 139 (analagous to herpes simplex virus type 1 histidine 58 and tyrosine 172), which may explain some of the differences in nucleoside sugar selectivity between both enzymes. The altered active site architecture may also account for the differences in the substrate activity of ganciclovir for the two thymidine kinases. These data should be of use in the design of novel antiherpes and antitumor drugs.
 
  Selected figure(s)  
 
Figure 1.
FIG. 1. Overall structure of VZV-tk. a, a representative 2F[o] - F[c] electron density map contoured at 1 showing residues 139-148 of the A subunit. b, simulated-annealing omit electron density map contoured at 3 showing the bound BVDU-MP and ADP in the A subunit. c, the two dimers in the crystal asymmetric unit. Protein chains are shown as ribbons and coils, and each monomer is colored differently. The bound BVDU-MPs and ADPs are shown as ball-and-sticks. The disulfide bridge between the two dimers is indicated by two orange spheres. d, Stereodiagram showing VZV-tk (blue) overlapped with HSV1-tk (magenta). Residue numbers at chain breaks are labeled.
Figure 4.
FIG. 4. Modeling of ganciclovir into the VZV-tk active site. a, overlap of GCV from HSV1-tk with BVDU-MP in the VZV-tk active site. The side chains of VZV-tk are colored in cyan, and BVDU-MP and GCV are shown as orange and dark gray ball-and-sticks, respectively. b, overlap of BVDU-MP in the VZV-tk active site with modeled GCV. The side chains of VZV-tk are colored in cyan, and BVDU-MP and GCV are shown as orange and dark gray ball-and-sticks, respectively.
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2003, 278, 24680-24687) copyright 2003.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
18384378 N.E.Mikkelsen, B.Munch-Petersen, and H.Eklund (2008).
Structural studies of nucleoside analog and feedback inhibitor binding to Drosophila melanogaster multisubstrate deoxyribonucleoside kinase.
  FEBS J, 275, 2151-2160.
PDB codes: 2jj8 2vp0 2vp2 2vp4 2vp5 2vp6 2vp9 2vqs
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.  
17062140 K.El Omari, N.Solaroli, A.Karlsson, J.Balzarini, and D.K.Stammers (2006).
Structure of vaccinia virus thymidine kinase in complex with dTTP: insights for drug design.
  BMC Struct Biol, 6, 22.
PDB code: 2j87
16522804 M.Kotaka, B.Dhaliwal, J.Ren, C.E.Nichols, R.Angell, M.Lockyer, A.R.Hawkins, and D.K.Stammers (2006).
Structures of S. aureus thymidylate kinase reveal an atypical active site configuration and an intermediate conformational state upon substrate binding.
  Protein Sci, 15, 774-784.
PDB codes: 2ccg 2ccj 2cck
15103156 C.E.Nichols, A.R.Hawkins, and D.K.Stammers (2004).
Structure of the 'open' form of Aspergillus nidulans 3-dehydroquinate synthase at 1.7 A resolution from crystals grown following enzyme turnover.
  Acta Crystallogr D Biol Crystallogr, 60, 971-973.
PDB code: 1sg6
15229896 C.E.Nichols, M.Lockyer, A.R.Hawkins, and D.K.Stammers (2004).
Crystal structures of Staphylococcus aureus type I dehydroquinase from enzyme turnover experiments.
  Proteins, 56, 625-628.
PDB codes: 1sfj 1sfl
15611477 M.Welin, U.Kosinska, N.E.Mikkelsen, C.Carnrot, C.Zhu, L.Wang, S.Eriksson, B.Munch-Petersen, and H.Eklund (2004).
Structures of thymidine kinase 1 of human and mycoplasmic origin.
  Proc Natl Acad Sci U S A, 101, 17970-17975.
PDB codes: 1xbt 1xmr 2uz3
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.