4EYI

Human DNA polymerase iota incorporating dATP opposite N-(deoxyguanosin-8-yl)-1-aminopyrene lesion

4EYI の概要

• エントリーDOI: 10.2210/pdb4eyi/pdb
• 関連するPDBエントリー: 4EYH
• 分子名称: DNA polymerase iota, DNA template, DNA primer, ... (6 entities in total)
• 機能のキーワード: dna polymerase, transferase-dna complex, transferase/dna
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Nucleus: Q9UNA4
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 52372.72

構造登録者

Kirouac, K.,Ling, H. (登録日: 2012-05-01, 公開日: 2013-01-09, 最終更新日: 2024-02-28)

主引用文献

Kirouac, K.N.,Basu, A.K.,Ling, H.
Replication of a carcinogenic nitropyrene DNA lesion by human Y-family DNA polymerase.
Nucleic Acids Res., 41:2060-2071, 2013

PubMed Abstract: Nitrated polycyclic aromatic hydrocarbons are common environmental pollutants, of which many are mutagenic and carcinogenic. 1-Nitropyrene is the most abundant nitrated polycyclic aromatic hydrocarbon, which causes DNA damage and is carcinogenic in experimental animals. Error-prone translesion synthesis of 1-nitropyrene-derived DNA lesions generates mutations that likely play a role in the etiology of cancer. Here, we report two crystal structures of the human Y-family DNA polymerase iota complexed with the major 1-nitropyrene DNA lesion at the insertion stage, incorporating either dCTP or dATP nucleotide opposite the lesion. Polι maintains the adduct in its active site in two distinct conformations. dCTP forms a Watson-Crick base pair with the adducted guanine and excludes the pyrene ring from the helical DNA, which inhibits replication beyond the lesion. By contrast, the mismatched dATP stacks above the pyrene ring that is intercalated in the helix and achieves a productive conformation for misincorporation. The intra-helical bulky pyrene mimics a base pair in the active site and facilitates adenine misincorporation. By structure-based mutagenesis, we show that the restrictive active site of human polη prevents the intra-helical conformation and A-base misinsertions. This work provides one of the molecular mechanisms for G to T transversions, a signature mutation in human lung cancer.

PubMed: 23268450
DOI: 10.1093/nar/gks1296

実験手法

X-RAY DIFFRACTION (2.9 Å)