Structures of human cytosolic and mitochondrial nucleotidases: implications for structure-based design of selective inhibitors

The human 5′(3′)‐deoxyribonucleotidases catalyze the dephosphorylation of deoxyribonucleoside monophosphates to the corresponding deoxyribonucleosides and thus help to maintain the balance between pools of nucleosides and nucleotides. Here, the structures of human cytosolic deoxyribonucleotidase (cd...

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Bibliographic Details
Published in:Acta crystallographica. Section D, Biological crystallography. Biological crystallography., 2014-02, Vol.70 (2), p.461-470
Main Authors: Pachl, Petr, Fábry, Milan, Rosenberg, Ivan, Šimák, Ondřej, Řezáčová, Pavlína, Brynda, Jiří
Format: Article
Language:English
Subjects:
5′(3′)-deoxyribonucleotidases
Catalytic Domain
Crystallography, X-Ray
Cytosol - chemistry
Cytosol - enzymology
Deoxyribonucleotides - chemistry
Drug Design
enzyme inhibition
Enzyme Inhibitors - chemistry
Escherichia coli - genetics
Escherichia coli - metabolism
Eukaryotic Cells - chemistry
Eukaryotic Cells - enzymology
Humans
hydrolases
Isoenzymes - antagonists & inhibitors
Isoenzymes - chemistry
Isoenzymes - genetics
Mitochondria - chemistry
Mitochondria - enzymology
Models, Molecular
Molecular Docking Simulation
Nucleotidases - antagonists & inhibitors
Nucleotidases - chemistry
Nucleotidases - genetics
Organ Specificity
Organophosphonates - chemistry
Phosphates - chemistry
Protein Conformation
Recombinant Proteins - chemistry
Recombinant Proteins - genetics
Structure-Activity Relationship
structure-based drug design
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Summary:The human 5′(3′)‐deoxyribonucleotidases catalyze the dephosphorylation of deoxyribonucleoside monophosphates to the corresponding deoxyribonucleosides and thus help to maintain the balance between pools of nucleosides and nucleotides. Here, the structures of human cytosolic deoxyribonucleotidase (cdN) at atomic resolution (1.08 Å) and mitochondrial deoxyribonucleotidase (mdN) at near‐atomic resolution (1.4 Å) are reported. The attainment of an atomic resolution structure allowed interatomic distances to be used to assess the probable protonation state of the phosphate anion and the side chains in the enzyme active site. A detailed comparison of the cdN and mdN active sites allowed the design of a cdN‐specific inhibitor.
ISSN:1399-0047
0907-4449
1399-0047
DOI:10.1107/S1399004713030502