6G0A

The crystal structure of the Pol2 catalytic domain of DNA polymerase epsilon carrying a P301R substitution.

6G0A の概要

• エントリーDOI: 10.2210/pdb6g0a/pdb
• 関連するPDBエントリー: 6fwk
• 分子名称: DNA polymerase epsilon catalytic subunit A, DNA (5'-D(P*TP*AP*AP*CP*CP*GP*CP*GP*TP*TP*DC)-3'), DNA (5'-D(P*TP*CP*TP*TP*GP*AP*AP*CP*GP*CP*GP*GP*TP*TP*A)-3'), ... (7 entities in total)
• 機能のキーワード: dna, pol2, pole, epsilon, p301r, cancer, dna binding protein
• 由来する生物種: Saccharomyces cerevisiae (strain ATCC 204508 / S288c); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 145756.02

構造登録者

Parkash, V.,Johansson, E. (登録日: 2018-03-16, 公開日: 2019-01-30, 最終更新日: 2024-01-17)

主引用文献

Parkash, V.,Kulkarni, Y.,Ter Beek, J.,Shcherbakova, P.V.,Kamerlin, S.C.L.,Johansson, E.
Structural consequence of the most frequently recurring cancer-associated substitution in DNA polymerase epsilon.
Nat Commun, 10:373-373, 2019

PubMed Abstract: The most frequently recurring cancer-associated DNA polymerase ε (Pol ε) mutation is a P286R substitution in the exonuclease domain. While originally proposed to increase genome instability by disrupting exonucleolytic proofreading, the P286R variant was later found to be significantly more pathogenic than Pol ε proofreading deficiency per se. The mechanisms underlying its stronger impact remained unclear. Here we report the crystal structure of the yeast orthologue, Pol ε-P301R, complexed with DNA and an incoming dNTP. Structural changes in the protein are confined to the exonuclease domain, with R301 pointing towards the exonuclease site. Molecular dynamics simulations suggest that R301 interferes with DNA binding to the exonuclease site, an outcome not observed with the exonuclease-inactive Pol ε-D290A,E292A variant lacking the catalytic residues. These results reveal a distinct mechanism of exonuclease inactivation by the P301R substitution and a likely basis for its dramatically higher mutagenic and tumorigenic effects.

PubMed: 30670696
DOI: 10.1038/s41467-018-08114-9

実験手法

X-RAY DIFFRACTION (2.62 Å)