1. Structures of human cytosolic and mitochondrial nucleotidases: implications for structure-based design of selective inhibitors
- Author
-
Milan Fábry, Pavlina Rezacova, Ondřej Šimák, Ivan Rosenberg, Jiří Brynda, and Petr Pachl
- Subjects
Models, Molecular ,Deoxyribonucleosides ,Protein Conformation ,Stereochemistry ,Deoxyribonucleotides ,Organophosphonates ,Protonation ,Crystallography, X-Ray ,Phosphates ,Structure-Activity Relationship ,Nucleotidases ,chemistry.chemical_compound ,Cytosol ,Structural Biology ,Catalytic Domain ,Hydrolase ,Escherichia coli ,Humans ,Nucleotide ,Enzyme Inhibitors ,chemistry.chemical_classification ,biology ,Chemistry ,Active site ,General Medicine ,Recombinant Proteins ,Mitochondria ,Isoenzymes ,Molecular Docking Simulation ,Deoxyribonucleoside ,Eukaryotic Cells ,Organ Specificity ,Drug Design ,biology.protein - Abstract
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.
- Published
- 2014