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PDBsum entry 3vtk

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Transferase PDB id
3vtk
Jmol
Contents
Protein chain
313 a.a. *
Ligands
ADP
5IU
Waters ×6
* Residue conservation analysis
PDB id:
3vtk
Name: Transferase
Title: Thymidine kinase from herpes simplex virus type 1 in complex and 5-iodo-deoxyuridine-monophosphate
Structure: Thymidine kinase. Chain: a. Engineered: yes
Source: Herpes simplex virus (type 1 / strain organism_taxid: 10304. Strain: f. Expressed in: escherichia coli. Expression_system_taxid: 562.
Biol. unit: Homo-Dimer (from PDB file)
Resolution:
3.00Å     R-factor:   0.222     R-free:   0.305
Authors: K.Wild,G.E.Schulz
Key ref:
K.Wild et al. (1997). The structures of thymidine kinase from herpes simplex virus type 1 in complex with substrates and a substrate analogue. Protein Sci, 6, 2097-2106. PubMed id: 9336833 DOI: 10.1002/pro.5560061005
Date:
01-Apr-97     Release date:   22-Oct-97    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P03176  (KITH_HHV11) -  Thymidine kinase
Seq:
Struc:
376 a.a.
313 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 = ADP)
corresponds exactly
+
thymidine 5'-phosphate
Bound ligand (Het Group name = 5IU)
matches with 90.91% 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: 10.1002/pro.5560061005 Protein Sci 6:2097-2106 (1997)
PubMed id: 9336833  
 
 
The structures of thymidine kinase from herpes simplex virus type 1 in complex with substrates and a substrate analogue.
K.Wild, T.Bohner, G.Folkers, G.E.Schulz.
 
  ABSTRACT  
 
Thymidine kinase from Herpes simplex virus type 1 (TK) was crystallized in an N-terminally truncated but fully active form. The structures of TK complexed with ADP at the ATP-site and deoxythymidine-5'-monophosphate (dTMP), deoxythymidine (dT), or idoxuridine-5'-phosphate (5-iodo-dUMP) at the substrate-site were refined to 2.75 A, 2.8 A, and 3.0 A resolution, respectively. TK catalyzes the phosphorylation of dT resulting in an ester, and the phosphorylation of dTMP giving rise to an anhydride. The presented TK structures indicate that there are only small differences between these two modes of action. Glu83 serves as a general base in the ester reaction. Arg163 parks at an internal aspartate during ester formation and binds the alpha-phosphate of dTMP during anhydride formation. The bound deoxythymidine leaves a 35 A3 cavity at position 5 of the base and two sequestered water molecules at position 2. Cavity and water molecules reduce the substrate specificity to such an extent that TK can phosphorylate various substrate analogues useful in pharmaceutical applications. TK is structurally homologous to the well-known nucleoside monophosphate kinases but contains large additional peptide segments.
 
  Selected figure(s)  
 
Figure 1.
ig. 1. Stereoviewofthesymmetric TK dimerwithboundADPanddTMP.Thedomainsaredefinedaccording to theNMP-kinases asCORE(residues 46-81,143-218.227-250.323-376, yellow, Wbi n,j (82-142, red), and ID (219-226, blue).The 72 additional residuesaroundosition 90 are green.Mobileparts are givenasdashedlines,thetwofold axis is inserted,secondary structures are defined in Fig. 2.
Figure 3.
Fig. 3. Final (2F0 - F,)-electron density maps or all substrates with the C trace of the P-loop as reference. All maps are contoured at the .0 (T level. A: ADPanddTPat 8, B: ADP and dTat 2.8 8, resolution. C: ADPand at 3.0 8, resolution.
 
  The above figures are reprinted from an Open Access publication published by the Protein Society: Protein Sci (1997, 6, 2097-2106) copyright 1997.  
  Figures were selected by an automated process.  

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.  
19858259 P.W.Krug, R.F.Schinazi, and J.K.Hilliard (2010).
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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.
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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
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.  
18459168 M.J.Pérez-Pérez, E.M.Priego, A.I.Hernández, O.Familiar, M.J.Camarasa, A.Negri, F.Gago, and J.Balzarini (2008).
Structure, physiological role, and specific inhibitors of human thymidine kinase 2 (TK2): present and future.
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16927131 C.Luo, A.Nawa, Y.Yamauchi, S.Kohno, Y.Ushijima, F.Goshima, F.Kikkawa, and Y.Nishiyama (2007).
Intercellular trafficking and cytotoxicity of recombinant HSV-1 thymidine kinase fused with HSV-2 US11 RXP repeat peptide.
  Virus Genes, 34, 263-272.  
17302737 L.Egeblad-Welin, Y.Sonntag, H.Eklund, and B.Munch-Petersen (2007).
Functional studies of active-site mutants from Drosophila melanogaster deoxyribonucleoside kinase. Investigations of the putative catalytic glutamate-arginine pair and of residues responsible for substrate specificity.
  FEBS J, 274, 1542-1551.
PDB code: 2jcs
17522225 M.I.Besecker, C.L.Furness, D.M.Coen, and A.Griffiths (2007).
Expression of extremely low levels of thymidine kinase from an acyclovir-resistant herpes simplex virus mutant supports reactivation from latently infected mouse trigeminal ganglia.
  J Virol, 81, 8356-8360.  
16775343 A.Griffiths, M.A.Link, C.L.Furness, and D.M.Coen (2006).
Low-level expression and reversion both contribute to reactivation of herpes simplex virus drug-resistant mutants with mutations on homopolymeric sequences in thymidine kinase.
  J Virol, 80, 6568-6574.  
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
16421443 Y.Zhang, J.A.Secrist, and S.E.Ealick (2006).
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PDB code: 2a7q
15526325 M.Kontoyianni, G.S.Sokol, and L.M.McClellan (2005).
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  J Comput Chem, 26, 11-22.  
16008571 M.Welin, T.Skovgaard, W.Knecht, C.Zhu, D.Berenstein, B.Munch-Petersen, J.Piskur, and H.Eklund (2005).
Structural basis for the changed substrate specificity of Drosophila melanogaster deoxyribonucleoside kinase mutant N64D.
  FEBS J, 272, 3733-3742.
PDB codes: 1zm7 1zmx
16103370 R.Chakrabarti, A.M.Klibanov, and R.A.Friesner (2005).
Sequence optimization and designability of enzyme active sites.
  Proc Natl Acad Sci U S A, 102, 12035-12040.  
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.  
14690426 J.F.Barroso, M.Elholm, and T.Flatmark (2003).
Tight binding of deoxyribonucleotide triphosphates to human thymidine kinase 2 expressed in Escherichia coli. Purification and partial characterization of its dimeric and tetrameric forms.
  Biochemistry, 42, 15158-15169.  
12205643 L.Salviati, S.Sacconi, M.Mancuso, D.Otaegui, P.Camaño, A.Marina, S.Rabinowitz, R.Shiffman, K.Thompson, C.M.Wilson, A.Feigenbaum, A.B.Naini, M.Hirano, E.Bonilla, S.DiMauro, and T.H.Vu (2002).
Mitochondrial DNA depletion and dGK gene mutations.
  Ann Neurol, 52, 311-317.  
12496124 M.Tramier, I.Gautier, T.Piolot, S.Ravalet, K.Kemnitz, J.Coppey, C.Durieux, V.Mignotte, and M.Coppey-Moisan (2002).
Picosecond-hetero-FRET microscopy to probe protein-protein interactions in live cells.
  Biophys J, 83, 3570-3577.  
12457846 R.G.Zhang, J.Grembecka, E.Vinokour, F.Collart, I.Dementieva, W.Minor, and A.Joachimiak (2002).
Structure of Bacillus subtilis YXKO--a member of the UPF0031 family and a putative kinase.
  J Struct Biol, 139, 161-170.
PDB code: 1kyh
11927571 W.Knecht, M.P.Sandrini, K.Johansson, H.Eklund, B.Munch-Petersen, and J.Piskur (2002).
A few amino acid substitutions can convert deoxyribonucleoside kinase specificity from pyrimidines to purines.
  EMBO J, 21, 1873-1880.  
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
11371472 I.Gautier, M.Tramier, C.Durieux, J.Coppey, R.B.Pansu, J.C.Nicolas, K.Kemnitz, and M.Coppey-Moisan (2001).
Homo-FRET microscopy in living cells to measure monomer-dimer transition of GFP-tagged proteins.
  Biophys J, 80, 3000-3008.  
11712095 R.T.Sarisky, R.Cano, T.T.Nguyen, R.J.Wittrock, K.E.Duffy, P.Clark, J.O.Bartus, T.H.Bacon, L.Caspers-Velu, R.L.Hodinka, and J.J.Leary (2001).
Biochemical characterization of a virus isolate, recovered from a patient with herpes keratitis, that was clinically resistant to acyclovir.
  Clin Infect Dis, 33, 2034-2039.  
11106599 A.Gorokhov, L.Perera, T.A.Darden, M.Negishi, L.C.Pedersen, and L.G.Pedersen (2000).
Heparan sulfate biosynthesis: a theoretical study of the initial sulfation step by N-deacetylase/N-sulfotransferase.
  Biophys J, 79, 2909-2917.  
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
10677210 I.J.MacRae, I.H.Segel, and A.J.Fisher (2000).
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  Biochemistry, 39, 1613-1621.
PDB code: 1d6j
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
10891066 N.Campobasso, I.I.Mathews, T.P.Begley, and S.E.Ealick (2000).
Crystal structure of 4-methyl-5-beta-hydroxyethylthiazole kinase from Bacillus subtilis at 1.5 A resolution.
  Biochemistry, 39, 7868-7877.
PDB codes: 1c3q 1ekk 1ekq 1esj 1esq
11123955 R.Zheng, and J.S.Blanchard (2000).
Identification of active site residues in E. coli ketopantoate reductase by mutagenesis and chemical rescue.
  Biochemistry, 39, 16244-16251.  
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.  
  10508017 F.Morfin, D.Thouvenot, M.De Turenne-Tessier, B.Lina, M.Aymard, and T.Ooka (1999).
Phenotypic and genetic characterization of thymidine kinase from clinical strains of varicella-zoster virus resistant to acyclovir.
  Antimicrob Agents Chemother, 43, 2412-2416.  
10606535 J.Wang, D.Choudhury, J.Chattopadhyaya, and S.Eriksson (1999).
Stereoisomeric selectivity of human deoxyribonucleoside kinases.
  Biochemistry, 38, 16993-16999.  
9548738 D.H.Harrison, J.A.Runquist, A.Holub, and H.M.Miziorko (1998).
The crystal structure of phosphoribulokinase from Rhodobacter sphaeroides reveals a fold similar to that of adenylate kinase.
  Biochemistry, 37, 5074-5085.
PDB code: 1a7j
9843365 I.I.Mathews, M.D.Erion, and S.E.Ealick (1998).
Structure of human adenosine kinase at 1.5 A resolution.
  Biochemistry, 37, 15607-15620.
PDB code: 1bx4
9715911 J.N.Champness, M.S.Bennett, F.Wien, R.Visse, W.C.Summers, P.Herdewijn, E.de Clerq, T.Ostrowski, R.L.Jarvest, and M.R.Sanderson (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.
PDB codes: 1ki2 1ki3 1ki4 1ki5 1ki6 1ki7 1ki8 1kim
  9658118 S.H.Chen, W.J.Cook, K.L.Grove, and D.M.Coen (1998).
Human thymidine kinase can functionally replace herpes simplex virus type 1 thymidine kinase for viral replication in mouse sensory ganglia and reactivation from latency upon explant.
  J Virol, 72, 6710-6715.  
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.