1LPQ

Human DNA Topoisomerase I (70 Kda) In Non-Covalent Complex With A 22 Base Pair DNA Duplex Containing an 8-oxoG Lesion

1LPQ の概要

• エントリーDOI: 10.2210/pdb1lpq/pdb
• 関連するPDBエントリー: 1A31 1A35 1A36 1EJ9
• 分子名称: 5'-D(*AP*AP*AP*AP*AP*GP*AP*CP*TP*TP*(8OG)P*GP*AP*AP*AP*AP*AP*TP*TP*TP*TP*T)-3', 5'-D(*AP*AP*AP*AP*AP*TP*TP*TP*TP*TP*CP*CP*AP*AP*GP*TP*CP*TP*TP*TP*TP*T)-3', DNA topoisomerase I, ... (4 entities in total)
• 機能のキーワード: protein-dna complex, dna damage, induced conformational change, isomerase-dna complex, isomerase/dna
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus, nucleolus: P11387
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 80279.89

構造登録者

Lesher, D.T.,Pommier, Y.,Stewart, L.,Redinbo, M.R. (登録日: 2002-05-08, 公開日: 2002-08-16, 最終更新日: 2024-02-14)

主引用文献

Lesher, D.T.,Pommier, Y.,Stewart, L.,Redinbo, M.R.
8-Oxoguanine rearranges the active site of human topoisomerase I
Proc.Natl.Acad.Sci.USA, 99:12102-12107, 2002

PubMed Abstract: 7,8-Dihydro-8-oxoguanine (8-oxoG) is the most common form of oxidative DNA damage in human cells. Biochemical studies have shown that 8-oxoG decreases the DNA cleavage activity of human topoisomerase I, an enzyme vital to DNA metabolism and stability. We present the 3.1-A crystal structure of human topoisomerase I in noncovalent complex with a DNA oligonucleotide containing 8-oxoG at the +1 position in the scissile strand. We find that 8-oxoG reorganizes the active site of human topoisomerase I into an inactive conformation relative to the structures of topoisomerase I-DNA complexes elucidated previously. The catalytic Tyr-723-Phe rotates away from the DNA cleavage site and packs into the body of the molecule. A second active-site residue, Arg-590, becomes disordered and is not observed in the structure. The docked, inactive conformation of Tyr-723-Phe is reminiscent of the related tyrosine recombinase family of integrases and recombinases, suggesting a common regulatory mechanism. We propose that human topoisomerase I binds to DNA first in an inactive conformation and then rearranges its active site for catalysis. 8-OxoG appears to impact topoisomerase I by stabilizing the inactive, DNA-bound state.

PubMed: 12209008
DOI: 10.1073/pnas.192282699

実験手法

X-RAY DIFFRACTION (3.14 Å)