5DQG

Crystal Structure of Human DNA Polymerase Eta Inserting dAMPNPP Opposite O4-Ethylthymidine

5DQG の概要

• エントリーDOI: 10.2210/pdb5dqg/pdb
• 関連するPDBエントリー: 5DLF 5DLG 5DQH 5DQI
• 分子名称: DNA polymerase eta, DNA (5'-D(*CP*AP*TP*(5EJ)P*AP*TP*GP*AP*CP*GP*CP*T)-3'), DNA (5'-D(*AP*GP*CP*GP*TP*CP*AP*T)-3'), ... (7 entities in total)
• 機能のキーワード: catalytic domain, dna damage, dna-directed dna polymerase, adenosine triphosphate, y-family polymerase, trans-lesion synthesis (tls), dna binding, o4-alkylthymidine, o4-ethylthymidine, transferase-dna complex, transferase/dna
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 55340.67

構造登録者

Patra, A.,OFlaherty, D.K.,Egli, M. (登録日: 2015-09-14, 公開日: 2016-08-10, 最終更新日: 2023-09-27)

主引用文献

O'Flaherty, D.K.,Patra, A.,Su, Y.,Guengerich, F.P.,Egli, M.,Wilds, C.J.
Lesion Orientation ofO4-Alkylthymidine Influences Replication by Human DNA Polymeraseeta.
Chem Sci, 7:4896-4904, 2016

PubMed Abstract: DNA lesions that elude repair may undergo translesion synthesis catalyzed by Y-family DNA polymerases. -Alkylthymidines, persistent adducts that can result from carcinogenic agents, may be encountered by DNA polymerases. The influence of lesion orientation around the C4- bond on processing by human DNA polymerase (hPol ) was studied for oligonucleotides containing -methylthymidine, -ethylthymidine, and analogs restricting the -methylene group in an -orientation. Primer extension assays revealed that the -alkyl orientation influences hPol bypass. Crystal structures of hPol •DNA•dNTP ternary complexes with -methyl- or -ethylthymidine in the template strand showed the nucleobase of the former lodged near the ceiling of the active site, with the --methyl group engaged in extensive hydrophobic interactions. This unique arrangement for -methylthymidine with hPol , inaccessible for the other analogs due to steric/conformational restriction, is consistent with differences observed for nucleotide incorporation and supports the concept that lesion conformation influences extension across DNA damage. Together, these results provide mechanistic insights on the mutagenicity of MedT and EtdT when acted upon by hPol .

PubMed: 27574558
DOI: 10.1039/C6SC00666C

実験手法

X-RAY DIFFRACTION (2.29 Å)