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PDBsum entry 1ki2

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protein ligands Protein-protein interface(s) links
Phosphotransferase PDB id
1ki2
Jmol
Contents
Protein chains
308 a.a. *
Ligands
SO4 ×2
GA2 ×2
Waters ×209
* Residue conservation analysis
PDB id:
1ki2
Name: Phosphotransferase
Title: Crystal structure of thymidine kinase from herpes simplex virus type i complexed with ganciclovir
Structure: Thymidine kinase. Chain: a, b. Synonym: tk. Engineered: yes
Source: Herpes simplex virus (type 1 / strain 17). Organism_taxid: 10299. Strain: 17. Gene: tk. Expressed in: escherichia coli. Expression_system_taxid: 562.
Biol. unit: Tetramer (from PQS)
Resolution:
2.20Å     R-factor:   0.192     R-free:   0.291
Authors: J.N.Champness,M.S.Bennett,F.Wien,D.G.Brown,R.Visse,G.Sandhu, A.Davies,P.J.Rizkallah,C.Melitz,W.C.Summers,M.R.Sanderson
Key ref: J.N.Champness et al. (1998). Exploring the active site of herpes simplex virus type-1 thymidine kinase by X-ray crystallography of complexes with aciclovir and other ligands. Proteins, 32, 350-361. PubMed id: 9715911
Date:
15-May-98     Release date:   02-Dec-98    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P03176  (KITH_HHV11) -  Thymidine kinase
Seq:
Struc:
376 a.a.
308 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
Bound ligand (Het Group name = GA2)
matches with 60.00% similarity
+ thymidine 5'-phosphate
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     TMP biosynthetic process   1 term 
  Biochemical function     ATP binding     2 terms  

 

 
    reference    
 
 
Proteins 32:350-361 (1998)
PubMed id: 9715911  
 
 
Exploring the active site of herpes simplex virus type-1 thymidine kinase by X-ray crystallography of complexes with aciclovir and other ligands.
J.N.Champness, M.S.Bennett, F.Wien, R.Visse, W.C.Summers, P.Herdewijn, E.de Clerq, T.Ostrowski, R.L.Jarvest, M.R.Sanderson.
 
  ABSTRACT  
 
Antiherpes therapies are principally targeted at viral thymidine kinases and utilize nucleoside analogs, the triphosphates of which are inhibitors of viral DNA polymerase or result in toxic effects when incorporated into DNA. The most frequently used drug, aciclovir (Zovirax), is a relatively poor substrate for thymidine kinase and high-resolution structural information on drugs and other molecules binding to the target is therefore important for the design of novel and more potent chemotherapy, both in antiherpes treatment and in gene therapy systems where thymidine kinase is expressed. Here, we report for the first time the binary complexes of HSV-1 thymidine kinase (TK) with the drug molecules aciclovir and penciclovir, determined by X-ray crystallography at 2.37 A resolution. Moreover, from new data at 2.14 A resolution, the refined structure of the complex of TK with its substrate deoxythymidine (R = 0.209 for 96% of all data) now reveals much detail concerning substrate and solvent interactions with the enzyme. Structures of the complexes of TK with four halogen-containing substrate analogs have also been solved, to resolutions better than 2.4 A. The various TK inhibitors broadly fall into three groups which together probe the space of the enzyme active site in a manner that no one molecule does alone, so giving a composite picture of active site interactions that can be exploited in the design of novel compounds.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21342564 K.C.Hsu, Y.F.Chen, S.R.Lin, and J.M.Yang (2011).
iGEMDOCK: a graphical environment of enhancing GEMDOCK using pharmacological interactions and post-screening analysis.
  BMC Bioinformatics, 12, S33.  
21143810 D.L.Clinciu, Y.F.Chen, C.N.Ko, C.C.Lo, and J.M.Yang (2010).
TSCC: Two-Stage Combinatorial Clustering for virtual screening using protein-ligand interactions and physicochemical features.
  BMC Genomics, 11, S26.  
20519201 Y.F.Chen, K.C.Hsu, S.R.Lin, W.C.Wang, Y.C.Huang, and J.M.Yang (2010).
SiMMap: a web server for inferring site-moiety map to recognize interaction preferences between protein pockets and compound moieties.
  Nucleic Acids Res, 38, W424-W430.  
19503928 Y.Mehellou, J.Balzarini, and C.McGuigan (2009).
An investigation into the anti-HIV activity of 2',3'-didehydro-2',3'-dideoxyuridine (d4U) and 2',3'-dideoxyuridine (ddU) phosphoramidate 'ProTide' derivatives.
  Org Biomol Chem, 7, 2548-2553.  
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.  
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
  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.  
17623865 V.Ramensky, A.Sobol, N.Zaitseva, A.Rubinov, and V.Zosimov (2007).
A novel approach to local similarity of protein binding sites substantially improves computational drug design results.
  Proteins, 69, 349-357.  
16702226 J.Balzarini, S.Liekens, N.Solaroli, K.El Omari, D.K.Stammers, and A.Karlsson (2006).
Engineering of a single conserved amino acid residue of herpes simplex virus type 1 thymidine kinase allows a predominant shift from pyrimidine to purine nucleoside phosphorylation.
  J Biol Chem, 281, 19273-19279.  
16532451 M.Y.Mizutani, Y.Takamatsu, T.Ichinose, K.Nakamura, and A.Itai (2006).
Effective handling of induced-fit motion in flexible docking.
  Proteins, 63, 878-891.  
15827202 G.Andrei, J.Balzarini, P.Fiten, E.De Clercq, G.Opdenakker, and R.Snoeck (2005).
Characterization of herpes simplex virus type 1 thymidine kinase mutants selected under a single round of high-dose brivudin.
  J Virol, 79, 5863-5869.  
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.  
15264251 H.Merlitz, T.Herges, and W.Wenzel (2004).
Fluctuation analysis and accuracy of a large-scale in silico screen.
  J Comput Chem, 25, 1568-1575.  
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
12616626 C.Monnerjahn, and M.Konrad (2003).
Modulated nucleoside kinases as tools to improve the activation of therapeutic nucleoside analogues.
  Chembiochem, 4, 143-146.  
12876373 G.Schuerman, K.Van Hecke, and L.Van Meervelt (2003).
Exploration of the influence of 5-iodo-2'-deoxyuridine incorporation on the structure of d[CACG(IDU)G].
  Acta Crystallogr D Biol Crystallogr, 59, 1525-1528.
PDB code: 1omk
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
  12869307 V.Ponomarev, M.Doubrovin, I.Serganova, T.Beresten, J.Vider, A.Shavrin, L.Ageyeva, J.Balatoni, R.Blasberg, and J.G.Tjuvajev (2003).
Cytoplasmically retargeted HSV1-tk/GFP reporter gene mutants for optimization of noninvasive molecular-genetic imaging.
  Neoplasia, 5, 245-254.  
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
11746690 J.L.Gelpí, S.G.Kalko, X.Barril, J.Cirera, X.de La Cruz, F.J.Luque, and M.Orozco (2001).
Classical molecular interaction potentials: improved setup procedure in molecular dynamics simulations of proteins.
  Proteins, 45, 428-437.  
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
10386936 J.Wouters, and P.Herdewijn (1999).
5-Substituted pyrimidine 1,5-anhydrohexitols: conformational analysis and interaction with viral thymidine kinase.
  Bioorg Med Chem Lett, 9, 1563-1566.  
10446143 M.Johansson, A.R.van Rompay, B.Degrève, J.Balzarini, and A.Karlsson (1999).
Cloning and characterization of the multisubstrate deoxyribonucleoside kinase of Drosophila melanogaster.
  J Biol Chem, 274, 23814-23819.  
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.