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PDBsum entry 1q91

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protein ligands metals links
Hydrolase PDB id
1q91
Jmol
Contents
Protein chain
194 a.a. *
Ligands
PO4
DPB
Metals
_MG
Waters ×328
* Residue conservation analysis
PDB id:
1q91
Name: Hydrolase
Title: Crystal structure of human mitochondrial deoxyribonucleotidase in complex with the inhibitor dpb-t
Structure: 5(3)-deoxyribonucleotidase. Chain: a. Synonym: deoxyribonucleotidase. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562
Biol. unit: Dimer (from PQS)
Resolution:
1.60Å     R-factor:   0.186     R-free:   0.206
Authors: A.Rinaldo-Matthis,C.Rampazzo,J.Balzarini,P.Reichard, V.Bianchi,P.Nordlund
Key ref: A.Rinaldo-Matthis et al. (2004). Crystal structures of the mitochondrial deoxyribonucleotidase in complex with two specific inhibitors. Mol Pharmacol, 65, 860-867. PubMed id: 15044615 DOI: 10.1124/mol.65.4.860
Date:
22-Aug-03     Release date:   20-Apr-04    
PROCHECK
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 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q9NPB1  (NT5M_HUMAN) -  5'(3')-deoxyribonucleotidase, mitochondrial
Seq:
Struc:
228 a.a.
194 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Biochemical function     phosphatase activity     1 term  

 

 
DOI no: 10.1124/mol.65.4.860 Mol Pharmacol 65:860-867 (2004)
PubMed id: 15044615  
 
 
Crystal structures of the mitochondrial deoxyribonucleotidase in complex with two specific inhibitors.
A.Rinaldo-Matthis, C.Rampazzo, J.Balzarini, P.Reichard, V.Bianchi, P.Nordlund.
 
  ABSTRACT  
 
Monophosphate nucleotidases are enzymes that dephosphorylate nucleotides to their corresponding nucleosides. They play potentially important roles in controlling the activation of nucleotide-based drugs targeted against viral infections or cancer cells. The human mitochondrial deoxyribonucleotidase (dNT-2) dephosphorylates thymidine and deoxyuridine monophosphates. We describe the high resolution structures of the dNT-2 enzyme in complex with two potent nucleoside phosphonate inhibitors, (S)-1-[2'-deoxy-3',5'-O-(1-phosphono) benzylidene-beta-d-threo-pentofuranosyl]thymine (DPB-T) at 1.6-A resolution and (+/-)-1-trans-(2-phosphonomethoxycyclopentyl)uracil (PMcP-U) at 1.4-A resolution. The mixed competitive inhibitor DPB-T and the competitive inhibitor PMcP-U both bind in the active site of dNT-2 but in distinctly different binding modes, explaining their different kinetics of inhibition. The pyrimidine part of the inhibitors binds with very similar hydrogen bond interactions to the protein but with their phosphonate moieties in different binding sites compared with each other and to the previously determined position of phosphate bound to dNT-2. Together, these phosphate/phosphonate binding sites describe what might constitute a functionally relevant phosphate entrance tunnel to the active site. The structures of the inhibitors in complex with dNT-2, being the first such complexes of any nucleotidase, might provide important information for the design of more specific inhibitors to control the activation of nucleotide-based drugs.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
15963349 S.A.Hunsucker, B.S.Mitchell, and J.Spychala (2005).
The 5'-nucleotidases as regulators of nucleotide and drug metabolism.
  Pharmacol Ther, 107, 1.  
15951836 W.Lewis, C.P.Haase, Y.K.Miller, B.Ferguson, T.Stuart, T.Ludaway, J.McNaught, R.Russ, J.Steltzer, R.Santoianni, R.Long, G.Fiermonte, and F.Palmieri (2005).
Transgenic expression of the deoxynucleotide carrier causes mitochondrial damage that is enhanced by NRTIs for AIDS.
  Lab Invest, 85, 972-981.  
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