6CVP

Human Aprataxin (Aptx) R199H bound to RNA-DNA, AMP and Zn product complex

6CVP の概要

• エントリーDOI: 10.2210/pdb6cvp/pdb
• 関連するPDBエントリー: 4NDF
• 分子名称: Aprataxin, DNA/RNA (5'-R(P*G)-D(P*TP*TP*AP*TP*GP*AP*TP*TP*C)-3'), DNA (5'-D(*GP*AP*AP*TP*CP*AP*TP*AP*AP*C)-3'), ... (7 entities in total)
• 機能のキーワード: protein-dna complex, dna repair, 5'-dna end processing, histidine triad domain, hit domain, zinc-finger, 5'-dna end recognition, hydrolase, hydrolase-dna-rna complex, hydrolase/dna/rna
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 55535.76

構造登録者

Schellenberg, M.J.,Williams, R.S.,Tumbale, P.S. (登録日: 2018-03-28, 公開日: 2018-07-04, 最終更新日: 2023-10-04)

主引用文献

Tumbale, P.,Schellenberg, M.J.,Mueller, G.A.,Fairweather, E.,Watson, M.,Little, J.N.,Krahn, J.,Waddell, I.,London, R.E.,Williams, R.S.
Mechanism of APTX nicked DNA sensing and pleiotropic inactivation in neurodegenerative disease.
EMBO J., 37:-, 2018

PubMed Abstract: The failure of DNA ligases to complete their catalytic reactions generates cytotoxic adenylated DNA strand breaks. The APTX RNA-DNA deadenylase protects genome integrity and corrects abortive DNA ligation arising during ribonucleotide excision repair and base excision DNA repair, and human mutations cause the neurodegenerative disorder ataxia with oculomotor ataxia 1 (AOA1). How APTX senses cognate DNA nicks and is inactivated in AOA1 remains incompletely defined. Here, we report X-ray structures of APTX engaging nicked RNA-DNA substrates that provide direct evidence for a wedge-pivot-cut strategy for 5'-AMP resolution shared with the alternate 5'-AMP processing enzymes POLβ and FEN1. Our results uncover a DNA-induced fit mechanism regulating APTX active site loop conformations and assembly of a catalytically competent active center. Further, based on comprehensive biochemical, X-ray and solution NMR results, we define a complex hierarchy for the differential impacts of the AOA1 mutational spectrum on APTX structure and activity. Sixteen AOA1 variants impact APTX protein stability, one mutation directly alters deadenylation reaction chemistry, and a dominant AOA1 variant unexpectedly allosterically modulates APTX active site conformations.

PubMed: 29934293
DOI: 10.15252/embj.201798875

実験手法

X-RAY DIFFRACTION (1.999 Å)