3B6O

Structure of TREX1 in complex with a nucleotide and an inhibitor ion (lithium)

3B6O の概要

• エントリーDOI: 10.2210/pdb3b6o/pdb
• 関連するPDBエントリー: 1Y97 2IOC 2O4G 2O4I 2OA8 3B6P
• 分子名称: Three prime repair exonuclease 1, LITHIUM ION, THYMIDINE-5'-PHOSPHATE, ... (4 entities in total)
• 機能のキーワード: trex1, dedd, exonuclease, dnaq, lithium, catalysis, inhibition, deoxy-thimidine monophosphate (dtmp), dna damage, dna repair, hydrolase, magnesium, nucleus, phosphorylation
• 由来する生物種: Mus musculus (Mouse)
• 細胞内の位置: Nucleus (By similarity): Q91XB0
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 110008.64

構造登録者

Brucet, M.,Querol-Audi, J.,Fita, I.,Celada, A. (登録日: 2007-10-29, 公開日: 2008-09-23, 最終更新日: 2023-08-30)

主引用文献

Brucet, M.,Querol-Audi, J.,Bertlik, K.,Lloberas, J.,Fita, I.,Celada, A.
Structural and biochemical studies of TREX1 inhibition by metals. Identification of a new active histidine conserved in DEDDh exonucleases.
Protein Sci., 17:2059-2069, 2008

PubMed Abstract: TREX1 is the major exonuclease in mammalian cells, exhibiting the highest level of activity with a 3'-->5' activity. This exonuclease is responsible in humans for Aicardi-Goutières syndrome and for an autosomal dominant retinal vasculopathy with cerebral leukodystrophy. In addition, this enzyme is associated with systemic lupus erythematosus. TREX1 belongs to the exonuclease DEDDh family, whose members display low levels of sequence identity, while possessing a common fold and active site organization. For these exonucleases, a catalytic mechanism has been proposed that involves two divalent metal ions bound to the DEDD motif. Here we studied the interaction of TREX1 with the monovalent cations lithium and sodium. We demonstrate that these metals inhibit the exonucleolytic activity of TREX1, as measured by the classical gel method, as well as by a new technique developed for monitoring the real-time exonuclease reaction. The X-ray structures of the enzyme in complex with these two cations and with a nucleotide, a product of the exonuclease reaction, were determined at 2.1 A and 2.3 A, respectively. A comparison with the structures of the active complexes (in the presence of magnesium or manganese) explains that the inhibition mechanism is caused by the noncatalytic metals competing with distinct affinities for the two metal-binding sites and inducing subtle rearrangements in active centers. Our analysis also reveals that a histidine residue (His124), highly conserved in the DEDDh family, is involved in the activity of TREX1, as confirmed by mutational studies. Our results shed further light on the mechanism of activity of the DEDEh family of exonucleases.

PubMed: 18780819
DOI: 10.1110/ps.036426.108

実験手法

X-RAY DIFFRACTION (2.1 Å)