2JAU

Crystal structure of D41N variant of human mitochondrial 5'(3')- deoxyribonucleotidase (mdN) in complex with 3'-azidothymidine 5'- monophosphate

2JAU の概要

• エントリーDOI: 10.2210/pdb2jau/pdb
• 関連するPDBエントリー: 1MH9 1Q91 1Q92 1Z4I 1Z4J 1Z4K 1Z4L 1Z4M 1Z4P 1Z4Q 2JAW
• 分子名称: 5'(3')-DEOXYRIBONUCLEOTIDASE, MAGNESIUM ION, PHOSPHATE ION, ... (5 entities in total)
• 機能のキーワード: transit peptide, nucleotide-binding, mitochondrial, metal-binding, alfa beta fold, nucleotide- binding, nucleotide metabolism, hydrolase, magnesium, mitochondrion
• 由来する生物種: HOMO SAPIENS (HUMAN)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 23330.94

構造登録者

Wallden, K.,Ruzzenente, B.,Bianchi, V.,Nordlund, P. (登録日: 2006-11-30, 公開日: 2007-12-11, 最終更新日: 2024-05-08)

主引用文献

Wallden, K.,Rinaldo-Matthis, A.,Ruzzenente, B.,Rampazzo, C.,Bianchi, V.,Nordlund, P.
Crystal Structures of Human and Murine Deoxyribonucleotidases: Insights Into Recognition of Substrates and Nucleotide Analogues.
Biochemistry, 46:13809-, 2007

PubMed Abstract: Cytosolic 5'(3')-deoxyribonucleotidase (cdN) and mitochondrial 5'(3')-deoxyribonucleotidase (mdN) catalyze the dephosphorylation of deoxyribonucleoside monophosphates and regulate dTTP formation in cytosol and mitochondria, protecting DNA replication from imbalanced precursor pools. They can also interfere with the phosphorylation-dependent activation of nucleoside analogues used in anticancer and antiviral treatment. To understand the relatively narrow substrate specificity of these two enzymes and their ability to use nucleotide analogues as substrates, we determined the crystal structures of human cdN in complex with deoxyuridine, murine cdN in complex with dUMP and dGMP, and human mdN in complex with the nucleotide analogues AZTMP and BVdUMP. Our results show that the active site residues Leu45 and Tyr65 in cdN form a more favorable binding surface for purine nucleotides than the corresponding Trp75 and Trp76 in mdN, explaining why cdN has higher activity for purine nucleotides than does mdN. The molecular interactions of mdN with AZTMP and BVdUMP indicate why these nucleotide analogues are poorer substrates as compared with the physiological substrate, and they provide a structural rationale for the design of drugs that are less prone to inactivation by the deoxyribonucleotidases. We suggest that introduction of substituents in the 3'-position may result in nucleoside analogues with increased resistance to dephosphorylation.

PubMed: 17985935
DOI: 10.1021/BI7014794

実験手法

X-RAY DIFFRACTION (1.8 Å)