Structures of human cytosolic and mitochondrial nucleotidases: implications for structure-based design of selective inhibitors
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
24531480
DOI
10.1107/s1399004713030502
PII: S1399004713030502
Knihovny.cz E-resources
- Keywords
- 5′(3′)-deoxyribonucleotidases, enzyme inhibition, hydrolases, structure-based drug design,
- MeSH
- Cytosol chemistry enzymology MeSH
- Deoxyribonucleotides chemistry MeSH
- Escherichia coli genetics metabolism MeSH
- Eukaryotic Cells chemistry enzymology MeSH
- Phosphates chemistry MeSH
- Enzyme Inhibitors chemistry MeSH
- Isoenzymes antagonists & inhibitors chemistry genetics MeSH
- Catalytic Domain MeSH
- Protein Conformation MeSH
- Crystallography, X-Ray MeSH
- Humans MeSH
- Mitochondria chemistry enzymology MeSH
- Models, Molecular MeSH
- Nucleotidases antagonists & inhibitors chemistry genetics MeSH
- Organophosphonates chemistry MeSH
- Organ Specificity MeSH
- Drug Design MeSH
- Recombinant Proteins chemistry genetics MeSH
- Molecular Docking Simulation MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Deoxyribonucleotides MeSH
- Phosphates MeSH
- Enzyme Inhibitors MeSH
- Isoenzymes MeSH
- Nucleotidases MeSH
- Organophosphonates MeSH
- Recombinant Proteins MeSH
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.
References provided by Crossref.org
PDB
4L57, 4L6A
