6SQY

Mouse dCTPase in complex with dCMP

6SQY の概要

• エントリーDOI: 10.2210/pdb6sqy/pdb
• 分子名称: dCTP pyrophosphatase 1, MAGNESIUM ION, 2'-DEOXYCYTIDINE-5'-MONOPHOSPHATE, ... (4 entities in total)
• 機能のキーワード: dcmp complex, hydrolase
• 由来する生物種: Mus musculus (House mouse)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 38244.77

構造登録者

Scaletti, E.R.,Claesson, M.,Helleday, H.,Jemth, A.S.,Stenmark, P. (登録日: 2019-09-04, 公開日: 2020-01-29, 最終更新日: 2024-05-15)

主引用文献

Scaletti, E.,Claesson, M.,Helleday, T.,Jemth, A.S.,Stenmark, P.
The First Structure of an Active Mammalian dCTPase and its Complexes With Substrate Analogs and Products.
J.Mol.Biol., 432:1126-1142, 2020

PubMed Abstract: Precise regulation of dNTPs within the cellular nucleotide pool is essential for high accuracy of DNA replication and is critical for retaining the genomic integrity. Recently, human dCTPase (deoxycytidine triphosphatase), also known as DCTPP1 (human all-alpha dCTP pyrophosphatase 1), has been revealed to be a key player in the balance of pyrimidine nucleotide concentrations within cells, with DCTPP1 deficiency causing DNA damage and genetic instability in both chromosomal and mitochondrial DNA. DCTPP1 also exhibits an additional "house cleaning" function as it has been shown to be highly active against modified cytidine triphosphates, such as 5-methyl-dCTP, which, if incorrectly incorporated into DNA can introduce undesirable epigenetic marking. To date, structural studies of mammalian dCTPase have been limited to inactive constructs, which do not provide information regarding the catalytic mechanism of this important enzyme. We present here the first structures of an active mammalian dCTPase from M. musculus in complex with the nonhydrolyzable substrate analog dCMPNPP and the products 5-Me-dCMP and dCMP. These structures provide clear insights into substrate binding and catalysis and clearly elucidate why previous structures of mammalian dCTPase were catalytically inactive. The overall structure of M. musculus dCTPase is highly similar to enzymes from the all-alpha NTP phosphohydrolase superfamily. Comparison of M. musculus dCTPase with homologs from a diverse range of mammals, including humans, shows that the residues, which contribute to substrate recognition, are entirely conserved, further supporting the importance of this enzyme in the protection of genomic integrity in mammalian cells.

PubMed: 31954130
DOI: 10.1016/j.jmb.2020.01.005

実験手法

X-RAY DIFFRACTION (1.9 Å)