PDBsum entry 1xmr

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protein ligands metals Protein-protein interface(s) links
Transferase PDB id
Protein chains
190 a.a.
207 a.a.
TTP ×4
_ZN ×4
_MG ×2
Waters ×144
Superseded by: 2uz3 2uz3
PDB id:
Name: Transferase
Title: Crystal structure of thymidine kinase with dttp from u. Urealyticum
Structure: Thymidine kinase. Chain: a, b, c, d. Engineered: yes. Mutation: yes
Source: Ureaplasma urealyticum. Bacteria. Gene: tdk. Expressed in: escherichia coli.
Biol. unit: Tetramer (from PQS)
2.50Å     R-factor:   0.225     R-free:   0.282
Authors: M.Welin,U.Kosinska,N.E.Mikkelsen,C.Carnrot,C.Zhu,L.Wang, S.Eriksson,B.Munch-Petersen,H.Eklund
Key ref:
M.Welin et al. (2004). Structures of thymidine kinase 1 of human and mycoplasmic origin. Proc Natl Acad Sci U S A, 101, 17970-17975. PubMed id: 15611477 DOI: 10.1073/pnas.0406332102
04-Oct-04     Release date:   14-Dec-04    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
Q9PPP5  (KITH_UREPA) -  Thymidine kinase
223 a.a.
190 a.a.*
Protein chains
Pfam   ArchSchema ?
Q9PPP5  (KITH_UREPA) -  Thymidine kinase
223 a.a.
207 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: Chains A, C: E.C.  - Thymidine kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + thymidine = ADP + thymidine 5'-phosphate
Bound ligand (Het Group name = TTP)
matches with 76.00% similarity
+ thymidine
+ thymidine 5'-phosphate
Molecule diagrams generated from .mol files obtained from the KEGG ftp site


DOI no: 10.1073/pnas.0406332102 Proc Natl Acad Sci U S A 101:17970-17975 (2004)
PubMed id: 15611477  
Structures of thymidine kinase 1 of human and mycoplasmic origin.
M.Welin, U.Kosinska, N.E.Mikkelsen, C.Carnrot, C.Zhu, L.Wang, S.Eriksson, B.Munch-Petersen, H.Eklund.
Cytosolic thymidine kinase 1, TK1, is a well known cell-cycle-regulated enzyme of importance in nucleotide metabolism as well as an activator of antiviral and anticancer drugs such as 3'-azido-3'-deoxythymidine (AZT). We have now determined the structures of the TK1 family, the human and Ureaplasma urealyticum enzymes, in complex with the feedback inhibitor dTTP. The TK1s have a tetrameric structure in which each subunit contains an alpha/beta-domain that is similar to ATPase domains of members of the RecA structural family and a domain containing a structural zinc. The zinc ion connects beta-structures at the root of a beta-ribbon that forms a stem that widens to a lasso-type loop. The thymidine of dTTP is hydrogen-bonded to main-chain atoms predominantly coming from the lasso loop. This binding is in contrast to other deoxyribonucleoside kinases where specific interactions occur with side chains. The TK1 structure differs fundamentally from the structures of the other deoxyribonucleoside kinases, indicating a different evolutionary origin.
  Selected figure(s)  
Figure 1.
Fig. 1. Structures of hTK1 and Uu-TK. (A) Structural alignment of the sequences of TKs from human (P04183 [GenBank] ), Dictyostelium discoideum (AAB03673 [GenBank] 1), Vaccinia virus (AAB96503 [GenBank] 1), B. cereus (ZP_00241105.1), E. coli (NP_287483 [GenBank] .1), and U. urealyticum (U. parvum) (NP_078433 [GenBank] ). Secondary structure elements for hTK1 are shown above the alignment in brown, and those for Uu-TK are shown below in green. The P loop and the two zinc coordinating sequences are boxed. (B) Subunit structure of hTK1 with dTTP colored according to atom type. Mg2+ is shown in yellow, and Zn2+ is shown in gray. (C) Subunit structure of Uu-TK with dTTP, Mg2+, and Zn2+ shown in same colors as in B. hTK1 and Uu-TK are tetramers. (D and E) hTK1 (D) and Uu-TK (E) tetramers shown in different views. The C-terminal helix in Uu-TK interacts with a helix on the adjacent monomer.
Figure 2.
Fig. 2. Lasso domain with structural Zn2+. The coordination of Zn2+ is shown as present in hTK1. In Uu-TK, the coordinating amino acids are C153, C156, C191, and H194. The lasso is shown in orange for hTK1. In Uu-TK, this loop is slightly longer (shown in green). Additionally, the hydrogen bonding from the conserved Arg-Tyr couple is shown.
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21303450 H.von Euler, and S.Eriksson (2011).
Comparative aspects of the proliferation marker thymidine kinase 1 in human and canine tumour diseases.
  Vet Comp Oncol, 9, 1.  
20860090 L.Wang, C.Hames, S.R.Schmidl, and J.Stülke (2010).
Upregulation of thymidine kinase activity compensates for loss of thymidylate synthase activity in Mycoplasma pneumoniae.
  Mol Microbiol, 77, 1502-1511.  
20652929 M.D.Bartholomä, A.R.Vortherms, S.Hillier, B.Ploier, J.Joyal, J.Babich, R.P.Doyle, and J.Zubieta (2010).
Synthesis, cytotoxicity, and insight into the mode of action of Re(CO)3 thymidine complexes.
  ChemMedChem, 5, 1513-1529.  
19087190 B.Munch-Petersen (2009).
Reversible tetramerization of human TK1 to the high catalytic efficient form is induced by pyrophosphate, in addition to tripolyphosphates, or high enzyme concentration.
  FEBS J, 276, 571-580.  
19474348 L.Liu, Y.Li, D.Liotta, and S.Lutz (2009).
Directed evolution of an orthogonal nucleoside analog kinase via fluorescence-activated cell sorting.
  Nucleic Acids Res, 37, 4472-4481.  
19283279 M.Bartholomä, J.Valliant, K.P.Maresca, J.Babich, and J.Zubieta (2009).
Single amino acid chelates (SAAC): a strategy for the design of technetium and rhenium radiopharmaceuticals.
  Chem Commun (Camb), (), 493-512.  
21582018 M.D.Bartholomä, W.Ouellette, and J.Zubieta (2009).
  Acta Crystallogr Sect E Struct Rep Online, 65, o432-o433.  
20119480 P.Lupieri, C.H.Nguyen, Z.G.Bafghi, A.Giorgetti, and P.Carloni (2009).
Computational molecular biology approaches to ligand-target interactions.
  HFSP J, 3, 228-239.  
20560637 S.K.Jarchow-Choy, E.Sjuvarsson, H.O.Sintim, S.Eriksson, and E.T.Kool (2009).
Nonpolar nucleoside mimics as active substrates for human thymidine kinases.
  J Am Chem Soc, 131, 5488-5494.  
  20305804 S.Lutz, L.Liu, and Y.Liu (2009).
Engineering Kinases to Phosphorylate Nucleoside Analogs for Antiviral and Cancer Therapy.
  Chimia (Aarau), 63, 737-744.  
21581365 M.D.Bartholomä, W.Ouellette, and J.Zubieta (2008).
2-(1,3-Dioxoisoindolin-2-yl)ethyl 4-methyl-benzene-sulfonate.
  Acta Crystallogr Sect E Struct Rep Online, 64, o2395.  
21581702 M.D.Bartholomä, W.Ouellette, and J.Zubieta (2008).
1-(Phthalimidometh-yl)pyridinium p-toluene-sulfonate.
  Acta Crystallogr Sect E Struct Rep Online, 65, o61.  
17525869 C.M.Hu, and Z.F.Chang (2007).
Mitotic control of dTTP pool: a necessity or coincidence?
  J Biomed Sci, 14, 491-497.  
18073106 D.Segura-Peña, J.Lichter, M.Trani, M.Konrad, A.Lavie, and S.Lutz (2007).
Quaternary structure change as a mechanism for the regulation of thymidine kinase 1-like enzymes.
  Structure, 15, 1555-1566.
PDB codes: 2qpo 2qq0 2qqe
17407781 D.Segura-Peña, S.Lutz, C.Monnerjahn, M.Konrad, and A.Lavie (2007).
Binding of ATP to TK1-like enzymes is associated with a conformational change in the quaternary structure.
  J Mol Biol, 369, 129-141.
PDB codes: 2orv 2orw
17530837 E.Sabini, S.Hazra, M.Konrad, and A.Lavie (2007).
Nonenantioselectivity property of human deoxycytidine kinase explained by structures of the enzyme in complex with L- and D-nucleosides.
  J Med Chem, 50, 3004-3014.
PDB codes: 2no0 2no1 2no6 2no7
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
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.  
17592850 S.Lutz, J.Lichter, and L.Liu (2007).
Exploiting temperature-dependent substrate promiscuity for nucleoside analogue activation by thymidine kinase from Thermotoga maritima.
  J Am Chem Soc, 129, 8714-8715.  
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
17581598 W.Knecht, E.Rozpedowska, C.Le Breton, M.Willer, Z.Gojkovic, M.P.Sandrini, T.Joergensen, L.Hasholt, B.Munch-Petersen, and J.Piskur (2007).
Drosophila deoxyribonucleoside kinase mutants with enhanced ability to phosphorylate purine analogs.
  Gene Ther, 14, 1278-1286.  
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.  
17132103 C.Carnrot, S.R.Vogel, Y.Byun, L.Wang, W.Tjarks, S.Eriksson, and A.J.Phipps (2006).
Evaluation of Bacillus anthracis thymidine kinase as a potential target for the development of antibacterial nucleoside analogs.
  Biol Chem, 387, 1575-1581.  
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
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
16336273 U.Kosinska, C.Carnrot, S.Eriksson, L.Wang, and H.Eklund (2005).
Structure of the substrate complex of thymidine kinase from Ureaplasma urealyticum and investigations of possible drug targets for the enzyme.
  FEBS J, 272, 6365-6372.
PDB code: 2b8t
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.