PDBsum entry 2b8t

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protein ligands metals Protein-protein interface(s) links
Transferase PDB id
Jmol PyMol
Protein chains
206 a.a. *
189 a.a. *
THM ×4
_ZN ×4
Waters ×230
* Residue conservation analysis
PDB id:
Name: Transferase
Title: Crystal structure of thymidine kinase from u.Urealyticum in complex with thymidine
Structure: Thymidine kinase. Chain: a, b, c, d. Engineered: yes
Source: Ureaplasma parvum. Organism_taxid: 134821. Gene: tdk. Expressed in: escherichia coli. Expression_system_taxid: 562.
Biol. unit: Tetramer (from PQS)
2.00Å     R-factor:   0.197     R-free:   0.235
Authors: U.Kosinska,C.Carnrot,S.Eriksson,L.Wang,H.Eklund
Key ref:
U.Kosinska et al. (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. PubMed id: 16336273 DOI: 10.1111/j.1742-4658.2005.05030.x
10-Oct-05     Release date:   20-Dec-05    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
Q9PPP5  (KITH_UREPA) -  Thymidine kinase
223 a.a.
206 a.a.*
Protein chain
Pfam   ArchSchema ?
Q9PPP5  (KITH_UREPA) -  Thymidine kinase
223 a.a.
189 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, B, C, D: E.C.  - Thymidine kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + thymidine = ADP + thymidine 5'-phosphate
Bound ligand (Het Group name = THM)
corresponds exactly
+ thymidine 5'-phosphate
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cytoplasm   1 term 
  Biological process     DNA biosynthetic process   3 terms 
  Biochemical function     nucleotide binding     6 terms  


DOI no: 10.1111/j.1742-4658.2005.05030.x FEBS J 272:6365-6372 (2005)
PubMed id: 16336273  
Structure of the substrate complex of thymidine kinase from Ureaplasma urealyticum and investigations of possible drug targets for the enzyme.
U.Kosinska, C.Carnrot, S.Eriksson, L.Wang, H.Eklund.
Thymidine kinases have been found in most organisms, from viruses and bacteria to mammals. Ureaplasma urealyticum (parvum), which belongs to the class of cell-wall-lacking Mollicutes, has no de novo synthesis of DNA precursors and therefore has to rely on the salvage pathway. Thus, thymidine kinase (Uu-TK) is the key enzyme in dTTP synthesis. Recently the 3D structure of Uu-TK was determined in a feedback inhibitor complex, demonstrating that a lasso-like loop binds the thymidine moiety of the feedback inhibitor by hydrogen bonding to main-chain atoms. Here the structure with the substrate deoxythymidine is presented. The substrate binds similarly to the deoxythymidine part of the feedback inhibitor, and the lasso-like loop binds the base and deoxyribose moieties as in the complex determined previously. The catalytic base, Glu97, has a different position in the substrate complex from that in the complex with the feedback inhibitor, having moved in closer to the 5'-OH of the substrate to form a hydrogen bond. The phosphorylation of and inhibition by several nucleoside analogues were investigated and are discussed in the light of the substrate binding pocket, in comparison with human TK1. Kinetic differences between Uu-TK and human TK1 were observed that may be explained by structural differences. The tight interaction with the substrate allows minor substitutions at the 3 and 5 positions of the base, only fluorine substitutions at the 2'-Ara position, but larger substitutions at the 3' position of the deoxyribose.
  Selected figure(s)  
Figure 1.
Fig. 1. (A) The structure of one subunit of Uu-TK (yellow) with conformations of the flexible loop as found in Uu-TK in complex with dT in subunit A (orange, A), Uu-TK in complex with dTTP (green, B) and in hTK1 in complex with dTTP (grey, C). The conformation of the loop shown in green (B) is very similar to that found in Ca-TK in complex with ADP as well as the loops in chains C and D of the Uu-TK–dT structure. (B) Superimposition of the nucleotide-binding region in the substrate complex (orange) and the inhibitor complex (olive). The side chain of the catalytic Glu97 has different positions in the two complexes. In the substrate complex, it is in a catalytically favourable position pointing inwards the active site. In the inhibitor complex, the side chain is repelled by the phosphates of the inhibitor.
Figure 2.
Fig. 2. Interactions between thymidine and Uu-TK. Hydrogen bonds are shown as dotted lines. The tight binding site for the 2' position between the main chain of Lys180-Ile181 and Met21. Any substitution at the 2' position hinders proper closure of the lasso, and thereby weakens substrate co-ordination.
  The above figures are reprinted by permission from the Federation of European Biochemical Societies: FEBS J (2005, 272, 6365-6372) copyright 2005.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20648496 J.Zander, M.Hartenfeller, V.Hähnke, E.Proschak, S.Besier, T.A.Wichelhaus, and G.Schneider (2010).
Multistep virtual screening for rapid and efficient identification of non-nucleoside bacterial thymidine kinase inhibitors.
  Chemistry, 16, 9630-9637.  
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.  
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.  
19995434 D.Lundin, E.Torrents, A.M.Poole, and B.M.Sjoberg (2009).
RNRdb, a curated database of the universal enzyme family ribonucleotide reductase, reveals a high level of misannotation in sequences deposited to Genbank.
  BMC Genomics, 10, 589.  
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.  
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
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
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
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.