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PDBsum entry 2ki5

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protein ligands Protein-protein interface(s) links
Transferase PDB id
2ki5
Jmol
Contents
Protein chains
304 a.a. *
Ligands
SO4 ×2
AC2 ×2
Waters ×292
* Residue conservation analysis
PDB id:
2ki5
Name: Transferase
Title: Herpes simplex type-1 thymidine kinase in complex with the drug aciclovir at 1.9a resolution
Structure: Protein (thymidine kinase). Chain: a, b. Synonym: tk. Engineered: yes. Other_details: aciclovir, antiviral drug as deposited in 1ki5
Source: Human herpesvirus 1. Herpes simplex virus type 1. Organism_taxid: 10298. Strain: sy211. Gene: tk. Expressed in: escherichia coli. Expression_system_taxid: 562.
Biol. unit: Homo-Dimer (from PDB file)
Resolution:
1.90Å     R-factor:   0.241     R-free:   0.317
Authors: M.S.Bennett,F.Wien,J.N.Champness,T.Batuwangala,T.Rutherford, W.C.Summers,H.Sun,G.Wright,M.R.Sanderson
Key ref:
M.S.Bennett et al. (1999). Structure to 1.9 A resolution of a complex with herpes simplex virus type-1 thymidine kinase of a novel, non-substrate inhibitor: X-ray crystallographic comparison with binding of aciclovir. FEBS Lett, 443, 121-125. PubMed id: 9989588 DOI: 10.1016/S0014-5793(98)01619-6
Date:
12-Feb-99     Release date:   04-Mar-99    
Supersedes: 1ki5
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P03176  (KITH_HHV11) -  Thymidine kinase
Seq:
Struc:
376 a.a.
304 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
Bound ligand (Het Group name = AC2)
matches with 57.00% similarity
= ADP
+ 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     5 terms  

 

 
    reference    
 
 
DOI no: 10.1016/S0014-5793(98)01619-6 FEBS Lett 443:121-125 (1999)
PubMed id: 9989588  
 
 
Structure to 1.9 A resolution of a complex with herpes simplex virus type-1 thymidine kinase of a novel, non-substrate inhibitor: X-ray crystallographic comparison with binding of aciclovir.
M.S.Bennett, F.Wien, J.N.Champness, T.Batuwangala, T.Rutherford, W.C.Summers, H.Sun, G.Wright, M.R.Sanderson.
 
  ABSTRACT  
 
Treatment of herpes infections with nucleoside analogues requires as an initial step the activation of the compounds by thymidine kinase. As an aid to developing more effective chemotherapy, both for treatment of recurrent herpes infection and in gene therapy systems where thymidine kinase is expressed, two high-resolution X-ray structures of thymidine kinase have been compared: one with the relatively poor substrate aciclovir (Zovirax), the other with a synthetic inhibitor having an N2-substituted guanine. Both compounds have similar binding modes in spite of their size difference and apparently distinct ligand properties.
 
  Selected figure(s)  
 
Figure 1.
Fig. 1. Stereo view of the binding of (A) aciclovir and (B) HBPG to TK (molecule 1) superimposed on a difference Fourier map contoured at 3×σ density and showing intermolecular hydrogen bonds. Owing to ambiguity in the density for the hydroxyethoxymethyl group of aciclovir (see text), two possible locations for the group are indicated in A.
Figure 2.
Fig. 2. Stereo view of the molecule 1 active site of the TK/HBPG complex (grey) overlaid on the active site of the TK/aciclovir complex (white) after alignment of enzyme molecules. (Water molecules in the HBPG complex are labelled ‘w'.)
 
  The above figures are reprinted by permission from the Federation of European Biochemical Societies: FEBS Lett (1999, 443, 121-125) copyright 1999.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
18196203 I.T.Hussein, R.N.Miguel, L.S.Tiley, and H.J.Field (2008).
Substrate specificity and molecular modelling of the feline herpesvirus-1 thymidine kinase.
  Arch Virol, 153, 495-505.  
  18949076 W.Candice L, S.Django, and B.Margaret E (2008).
The role of herpes simplex virus-1 thymidine kinase alanine 168 in substrate specificity.
  Open Biochem J, 2, 60-66.  
15916444 A.Manikowski, A.Verri, A.Lossani, B.M.Gebhardt, J.Gambino, F.Focher, S.Spadari, and G.E.Wright (2005).
Inhibition of herpes simplex virus thymidine kinases by 2-phenylamino-6-oxopurines and related compounds: structure-activity relationships and antiherpetic activity in vivo.
  J Med Chem, 48, 3919-3929.  
15153115 H.Frederiksen, D.Berenstein, and B.Munch-Petersen (2004).
Effect of valine 106 on structure-function relation of cytosolic human thymidine kinase. Kinetic properties and oligomerization pattern of nine substitution mutants of V106.
  Eur J Biochem, 271, 2248-2256.  
15163659 P.Schelling, M.T.Claus, R.Johner, V.E.Marquez, G.E.Schulz, and L.Scapozza (2004).
Biochemical and structural characterization of (South)-methanocarbathymidine that specifically inhibits growth of herpes simplex virus type 1 thymidine kinase-transduced osteosarcoma cells.
  J Biol Chem, 279, 32832-32838.
PDB code: 1of1
12454011 A.Haouz, V.Vanheusden, H.Munier-Lehmann, M.Froeyen, P.Herdewijn, S.Van Calenbergh, and M.Delarue (2003).
Enzymatic and structural analysis of inhibitors designed against Mycobacterium tuberculosis thymidylate kinase. New insights into the phosphoryl transfer mechanism.
  J Biol Chem, 278, 4963-4971.
PDB codes: 1mrn 1mrs
12686543 L.E.Bird, J.Ren, A.Wright, K.D.Leslie, B.Degrève, J.Balzarini, and D.K.Stammers (2003).
Crystal structure of varicella zoster virus thymidine kinase.
  J Biol Chem, 278, 24680-24687.
PDB code: 1osn
11266595 C.Wurth, U.Kessler, J.Vogt, G.E.Schulz, G.Folkers, and L.Scapozza (2001).
The effect of substrate binding on the conformation and structural stability of Herpes simplex virus type 1 thymidine kinase.
  Protein Sci, 10, 63-73.
PDB codes: 1e2m 1e2n 1e2p
11392548 S.Manfredini, P.G.Baraldi, E.Durini, L.Porcu, A.Angusti, S.Vertuani, N.Solaroli, E.De Clercq, A.Karlsson, and J.Balzarini (2001).
Design, synthesis and enzymatic activity of highly selective human mitochondrial thymidine kinase inhibitors.
  Bioorg Med Chem Lett, 11, 1329-1332.  
10924157 A.Prota, J.Vogt, B.Pilger, R.Perozzo, C.Wurth, V.E.Marquez, P.Russ, G.E.Schulz, G.Folkers, and L.Scapozza (2000).
Kinetics and crystal structure of the wild-type and the engineered Y101F mutant of Herpes simplex virus type 1 thymidine kinase interacting with (North)-methanocarba-thymidine.
  Biochemistry, 39, 9597-9603.
PDB codes: 1e2k 1e2l
11056041 J.Vogt, R.Perozzo, A.Pautsch, A.Prota, P.Schelling, B.Pilger, G.Folkers, L.Scapozza, and G.E.Schulz (2000).
Nucleoside binding site of herpes simplex type 1 thymidine kinase analyzed by X-ray crystallography.
  Proteins, 41, 545-553.
PDB codes: 1e2h 1e2i 1e2j
10747801 T.A.Hinds, C.Compadre, B.K.Hurlburt, and R.R.Drake (2000).
Conservative mutations of glutamine-125 in herpes simplex virus type 1 thymidine kinase result in a ganciclovir kinase with minimal deoxypyrimidine kinase activities.
  Biochemistry, 39, 4105-4111.  
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 code is shown on the right.