PDBsum entry 2cck

Go to PDB code: 
protein ligands metals Protein-protein interface(s) links
Transferase PDB id
Protein chains
193 a.a. *
_CL ×5
Waters ×216
* Residue conservation analysis
PDB id:
Name: Transferase
Title: Crystal structure of unliganded s. Aureus thymidylate kinase
Structure: Thymidylate kinase. Chain: a, b. Synonym: dtmp kinase. Engineered: yes
Source: Staphylococcus aureus. Organism_taxid: 1280. Expressed in: escherichia coli. Expression_system_taxid: 469008.
Biol. unit: Dimer (from PDB file)
2.21Å     R-factor:   0.197     R-free:   0.255
Authors: M.Kotaka,B.Dhaliwal,J.Ren,C.E.Nichols,R.Angell,M.Lockyer, A.R.Hawkins,D.K.Stammers
Key ref:
M.Kotaka et al. (2006). Structures of S. aureus thymidylate kinase reveal an atypical active site configuration and an intermediate conformational state upon substrate binding. Protein Sci, 15, 774-784. PubMed id: 16522804 DOI: 10.1110/ps.052002406
16-Jan-06     Release date:   08-Mar-06    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
P65248  (KTHY_STAAM) -  Thymidylate kinase
205 a.a.
193 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.  - dTMP kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + dTMP = ADP + dTDP
+ dTMP
+ dTDP
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     phosphorylation   5 terms 
  Biochemical function     nucleotide binding     5 terms  


DOI no: 10.1110/ps.052002406 Protein Sci 15:774-784 (2006)
PubMed id: 16522804  
Structures of S. aureus thymidylate kinase reveal an atypical active site configuration and an intermediate conformational state upon substrate binding.
M.Kotaka, B.Dhaliwal, J.Ren, C.E.Nichols, R.Angell, M.Lockyer, A.R.Hawkins, D.K.Stammers.
Methicillin-resistant Staphylococcus aureus (MRSA) poses a major threat to human health, particularly through hospital acquired infection. The spread of MRSA means that novel targets are required to develop potential inhibitors to combat infections caused by such drug-resistant bacteria. Thymidylate kinase (TMK) is attractive as an antibacterial target as it is essential for providing components for DNA synthesis. Here, we report crystal structures of unliganded and thymidylate-bound forms of S. aureus thymidylate kinase (SaTMK). His-tagged and untagged SaTMK crystallize with differing lattice packing and show variations in conformational states for unliganded and thymidylate (TMP) bound forms. In addition to open and closed forms of SaTMK, an intermediate conformation in TMP binding is observed, in which the site is partially closed. Analysis of these structures indicates a sequence of events upon TMP binding, with helix alpha3 shifting position initially, followed by movement of alpha2 to close the substrate site. In addition, we observe significant conformational differences in the TMP-binding site in SaTMK as compared to available TMK structures from other bacterial species, Escherichia coli and Mycobacterium tuberculosis as well as human TMK. In SaTMK, Arg 48 is situated at the base of the TMP-binding site, close to the thymine ring, whereas a cis-proline occupies the equivalent position in other TMKs. The observed TMK structural differences mean that design of compounds highly specific for the S. aureus enzyme looks possible; such inhibitors could minimize the transfer of drug resistance between different bacterial species.
  Selected figure(s)  
Figure 3.
Figure 3 TMP-induced conformational change of SaTMK. (A) Stereo view of the alignmentof C traces of unliganded SaTMK (gray); TMP site partially closed SaTMK (yellow) and TMP site closed SaTMK (red). The N and C termini are indicated by green and by magenta spheres, respectively. The helices 2and 3 are labeled in magenta. Hinge points of the LID regions (labeled in blue) as identified with TAD analysis are drawn as black spheres and labeled in red. Flexible loops with torsion angle differences identified by TAD analysis are labeled in italics. (B) TAD plot of comparison of torsion angles between unliganded and TMP site closed SaTMK. The significant TAD peaks are labeled in black and correspond to the loops in A. The LID region is labeled in blue. The hinge points of the LID region are labeled as H1 and H2 in red. (C) Close-up stereo view of TMP-binding site. Residues are drawn in gray for unliganded SaTMK, in yellow for the SaTMK with partially closed TMP site, and in red for TMP site closed SaTMK.
  The above figure is reprinted by permission from the Protein Society: Protein Sci (2006, 15, 774-784) copyright 2006.  
  Figure was selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20353400 J.L.Whittingham, J.Carrero-Lerida, J.A.Brannigan, L.M.Ruiz-Perez, A.P.Silva, M.J.Fogg, A.J.Wilkinson, I.H.Gilbert, K.S.Wilson, and D.González-Pacanowska (2010).
Structural basis for the efficient phosphorylation of AZT-MP (3'-azido-3'-deoxythymidine monophosphate) and dGMP by Plasmodium falciparum type I thymidylate kinase.
  Biochem J, 428, 499-509.
PDB codes: 2wwf 2wwg 2wwh 2wwi
19126267 M.Kandeel, T.Ando, Y.Kitamura, M.Abdel-Aziz, and Y.Kitade (2009).
Mutational, inhibitory and microcalorimetric analyses of Plasmodium falciparum TMP kinase. Implications for drug discovery.
  Parasitology, 136, 11-25.  
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
18523102 C.Carnrot, L.Wang, D.Topalis, and S.Eriksson (2008).
Mechanisms of substrate selectivity for Bacillus anthracis thymidylate kinase.
  Protein Sci, 17, 1486-1493.  
  17012781 K.El Omari, B.Dhaliwal, M.Lockyer, I.Charles, A.R.Hawkins, and D.K.Stammers (2006).
Structure of Staphylococcus aureus guanylate monophosphate kinase.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 62, 949-953.
PDB code: 2j41
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.