title: Structures of human cytosolic and mitochondrial nucleotidases: implications for structure-based design of selective inhibitors.
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.
authors: Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nám. 2, 166 37 Prague 6, Czech Republic.
authors: Petr
authors: P
authors: Pachl
authors: Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nám. 2, 166 37 Prague 6, Czech Republic.
authors: Milan
authors: M
authors: Fábry
authors: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nám. 2, 166 37 Prague 6, Czech Republic.
authors: Ivan
authors: I
authors: Rosenberg
authors: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nám. 2, 166 37 Prague 6, Czech Republic.
authors: Ondřej
authors: O
authors: Simák
authors: Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nám. 2, 166 37 Prague 6, Czech Republic.
authors: Pavlína
authors: P
authors: Rezáčová
authors: Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nám. 2, 166 37 Prague 6, Czech Republic.
authors: Jiří
authors: J
authors: Brynda
mesh_terms: D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D003600:Cytosol / Q000737:chemistry / Q000201:enzymology; D003854:Deoxyribonucleotides / Q000737:chemistry*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry*; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D005057:Eukaryotic Cells / Q000737:chemistry / Q000201:enzymology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D008928:Mitochondria / Q000737:chemistry / Q000201:enzymology; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D009708:Nucleotidases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D009928:Organ Specificity; D063065:Organophosphonates / Q000737:chemistry*; D010710:Phosphates / Q000737:chemistry*; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D013329:Structure-Activity Relationship
chemical_list: D003854:Deoxyribonucleotides; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D063065:Organophosphonates; D010710:Phosphates; D011994:Recombinant Proteins; D009708:Nucleotidases
keywords: 5′(3′)-deoxyribonucleotidases; enzyme inhibition; hydrolases; structure-based drug design