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PDBsum entry 2j0f

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protein ligands Protein-protein interface(s) links
Transferase PDB id
2j0f
Jmol
Contents
Protein chains
446 a.a. *
Ligands
TDR ×3
Waters ×450
* Residue conservation analysis
PDB id:
2j0f
Name: Transferase
Title: Structural basis for non-competitive product inhibition in human thymidine phosphorylase: implication for drug design
Structure: Thymidine phosphorylase. Chain: a, b, c, d. Synonym: tdrpase, tp, platelet-derived endothelial cell growth factor, gliostatin, pd-ecgf. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562
Biol. unit: Dimer (from PDB file)
Resolution:
2.31Å     R-factor:   0.248     R-free:   0.287
Authors: K.El Omari,A.Bronckaers,S.Liekens,M.J.Perez-Perez, J.Balzarini,D.K.Stammers
Key ref: K.El Omari et al. (2006). Structural basis for non-competitive product inhibition in human thymidine phosphorylase: implications for drug design. Biochem J, 399, 199-204. PubMed id: 16803458 DOI: 10.1042/BJ20060513
Date:
02-Aug-06     Release date:   11-Oct-06    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P19971  (TYPH_HUMAN) -  Thymidine phosphorylase
Seq:
Struc:
482 a.a.
446 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 3 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.2.4.2.4  - Thymidine phosphorylase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Thymidine + phosphate = thymine + 2-deoxy-alpha-D-ribose 1-phosphate
Thymidine
+ phosphate
=
thymine
Bound ligand (Het Group name = TDR)
corresponds exactly
+ 2-deoxy-alpha-D-ribose 1-phosphate
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cytosol   1 term 
  Biological process     metabolic process   14 terms 
  Biochemical function     transferase activity     8 terms  

 

 
    reference    
 
 
DOI no: 10.1042/BJ20060513 Biochem J 399:199-204 (2006)
PubMed id: 16803458  
 
 
Structural basis for non-competitive product inhibition in human thymidine phosphorylase: implications for drug design.
K.El Omari, A.Bronckaers, S.Liekens, M.J.Pérez-Pérez, J.Balzarini, D.K.Stammers.
 
  ABSTRACT  
 
HTP (human thymidine phosphorylase), also known as PD-ECGF (platelet-derived endothelial cell growth factor) or gliostatin, has an important role in nucleoside metabolism. HTP is implicated in angiogenesis and apoptosis and therefore is a prime target for drug design, including antitumour therapies. An HTP structure in a closed conformation complexed with an inhibitor has previously been solved. Earlier kinetic studies revealed an ordered release of thymine followed by ribose phosphate and product inhibition by both ligands. We have determined the structure of HTP from crystals grown in the presence of thymidine, which, surprisingly, resulted in bound thymine with HTP in a closed dead-end complex. Thus thymine appears to be able to reassociate with HTP after its initial ordered release before ribose phosphate and induces the closed conformation, hence explaining the mechanism of non-competitive product inhibition. In the active site in one of the four HTP molecules within the crystal asymmetric unit, additional electron density is present. This density has not been previously seen in any pyrimidine nucleoside phosphorylase and it defines a subsite that may be exploitable in drug design. Finally, because our crystals did not require proteolysed HTP to grow, the structure reveals a loop (residues 406-415), disordered in the previous HTP structure. This loop extends across the active-site cleft and appears to stabilize the dimer interface and the closed conformation by hydrogen-bonding. The present study will assist in the design of HTP inhibitors that could lead to drugs for anti-angiogenesis as well as for the potentiation of other nucleoside drugs.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
19434693 A.Bronckaers, F.Gago, J.Balzarini, and S.Liekens (2009).
The dual role of thymidine phosphorylase in cancer development and chemotherapy.
  Med Res Rev, 29, 903-953.  
19555658 E.Mitsiki, A.C.Papageorgiou, S.Iyer, N.Thiyagarajan, S.H.Prior, D.Sleep, C.Finnis, and K.R.Acharya (2009).
Structures of native human thymidine phosphorylase and in complex with 5-iodouracil.
  Biochem Biophys Res Commun, 386, 666-670.
PDB codes: 2wk5 2wk6
17869163 V.L.Schramm (2007).
Binding isotope effects: boon and bane.
  Curr Opin Chem Biol, 11, 529-536.  
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