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

0435088 - ÚMG 2015 RIV DK eng J - Journal Article
Pachl, Petr - Fábry, Milan - Rosenberg, Ivan - Šimák, Ondřej - Řezáčová, Pavlína - Brynda, Jiří
Structures of human cytosolic and mitochondrial nucleotidases: implications for structure-based design of selective inhibitors.
Acta Crystallographica Section D-Biological Crystallography. Roč. 70, February (2014), s. 461-470. ISSN 0907-4449
R&D Projects: GA ČR GA203/09/0820
Institutional support: RVO:68378050 ; RVO:61388963
Keywords : 5′(3′)-deoxyribonucleotidases * enzyme inhibition * hydrolases * structure-based drug design
Subject RIV: EB - Genetics ; Molecular Biology
Impact factor: 7.232, year: 2013

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 odeoxyribonucleotidase (cdN) at atomic resolution (1.08 angstrom) and mitochondrial deoxyribonucleotidase (mdN) at near-atomic resolution (1.4 angstrom) 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.
Permanent Link: http://hdl.handle.net/11104/0241981