6MXO

Structure of HPoleta incorporating dCTP opposite the 3-prime Pt(DACH)-GG

6MXO の概要

• エントリーDOI: 10.2210/pdb6mxo/pdb
• 関連するPDBエントリー: 4DL2 4DL3 4DL4 4DL5
• 分子名称: DNA polymerase eta, DNA (5'-D(*AP*CP*GP*GP*CP*TP*CP*AP*CP*AP*CP*T)-3'), DNA (5'-D(*TP*AP*GP*TP*GP*TP*GP*AP*G)-3'), ... (8 entities in total)
• 機能のキーワード: y-family dna polymerase, pt(dach)-gg, transferase-dna-inhibitor complex, nuclear protein, nuclear protein-dna complex, nuclear protein/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: 56983.14

構造登録者

Ouzon-Shubeita, H.,Lee, S. (登録日: 2018-10-31, 公開日: 2019-02-13, 最終更新日: 2023-10-11)

主引用文献

Ouzon-Shubeita, H.,Baker, M.,Koag, M.C.,Lee, S.
Structural basis for the bypass of the major oxaliplatin-DNA adducts by human DNA polymerase eta.
Biochem. J., 476:747-758, 2019

PubMed Abstract: Oxaliplatin, together with cisplatin, is among the most important drugs used in cancer chemotherapy. Oxaliplatin, which contains a bulky diaminocyclohexane (DACH) moiety, kills cancer cells mainly by producing (DACH)Pt-GpG intrastrand cross-links that impede transcription. The Pt-GpG tolerance by translesion DNA synthesis (TLS) polymerases contributes to the resistance of tumors to platinum-based chemotherapy. In particular, human DNA polymerase η (Polη) readily bypasses Pt-GpG adducts. While many structural studies have addressed how TLS polymerases interact with cisplatin-DNA adducts, a structure of DNA polymerase in complex with oxaliplatin-DNA adducts has not been reported, limiting our understanding of bypass of the bulky (DACH)Pt-GpG lesion by TLS polymerases. Herein, we report the first structure of DNA polymerase bound to oxaliplatinated DNA. We determined a crystal structure of Polη incorporating dCTP opposite the 3'G of the (DACH)Pt-GpG, which provides insights into accurate, efficient bypass of the oxaliplatin-GpG adducts by TLS polymerases. In the catalytic site of Polη, the 3'G of the (DACH)Pt-GpG formed three Watson-Crick hydrogen bonds with incoming dCTP and the primer terminus 3'-OH was optimally positioned for nucleotidyl transfer. To accommodate the bulky (DACH)Pt-GpG lesion, the Val59-Trp64 loop in the finger domain of Polη shifted from the positions observed in the corresponding Polη-cisplatin-GpG and undamaged structures, suggesting that the flexibility of the Val59-Trp64 loop allows the enzyme's bypass of the (DACH)Pt-GpG adducts. Overall, the Polη-oxaliplatin-GpG structure provides a structural basis for TLS-mediated bypass of the major oxaliplatin-DNA adducts and insights into resistance to platinum-based chemotherapy in humans.

PubMed: 30709915
DOI: 10.1042/BCJ20180848

実験手法

X-RAY DIFFRACTION (2.04 Å)