1SC7

Human DNA Topoisomerase I (70 Kda) In Complex With The Indenoisoquinoline MJ-II-38 and Covalent Complex With A 22 Base Pair DNA Duplex

1SC7 の概要

• エントリーDOI: 10.2210/pdb1sc7/pdb
• 関連するPDBエントリー: 1K4S 1K4T
• 分子名称: 5'-D(*AP*AP*AP*AP*AP*GP*AP*CP*TP*T)-3', 5'-D(*(TGP)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', ... (6 entities in total)
• 機能のキーワード: complex (isomerase-dna), dna, topoisomerase i, drug, poison, idenoisoquinoline, 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: 4
• 化学式量合計: 84243.52

構造登録者

Staker, B.L.,Feese, M.D.,Cushman, M.,Pommier, Y.,Zembower, D.,Stewart, L.,Burgin, A.B. (登録日: 2004-02-11, 公開日: 2005-04-19, 最終更新日: 2024-11-20)

主引用文献

Staker, B.L.,Feese, M.D.,Cushman, M.,Pommier, Y.,Zembower, D.,Stewart, L.,Burgin, A.B.
Structures of three classes of anticancer agents bound to the human topoisomerase I-DNA covalent complex
J.Med.Chem., 48:2336-2345, 2005

PubMed Abstract: Human topoisomerase I (top1) is the molecular target of a diverse set of anticancer compounds, including the camptothecins, indolocarbazoles, and indenoisoquinolines. These compounds bind to a transient top1-DNA covalent complex and inhibit the resealing of a single-strand nick that the enzyme creates to relieve superhelical tension in duplex DNA. (Hertzberg, R. P.; et al. Biochem. 1989, 28, 4629-4638. Hsiang, Y. H.; et al. J. Biol. Chem 1985, 260, 14873-14878. Champoux, J. J. Annu. Rev. Biochem. 2001, 70, 369-413. Stewart, L.; et al. Science 1998, 729, 1534-1541.) We report the X-ray crystal structures of the human top1-DNA complex bound with camptothecin and representative members of the indenoisoquinoline and indolocarbazole classes of top1 poisons. The planar nature of all three structurally diverse classes allows them to intercalate between DNA base pairs at the site of single-strand cleavage. All three classes of compounds have a free electron pair near Arg364, a residue that if mutated confers resistance to all three classes of drugs. The common intercalative binding mode is augmented by unexpected chemotype-specific contacts with amino acid residues Asn352 and Glu356, which adopt alternative side-chain conformations to accommodate the bound compounds. These new X-ray structures explain how very different molecules can stabilize top1-DNA covalent complexes and will aid the rational design of completely novel structural classes of anticancer drugs.

PubMed: 15801827
DOI: 10.1021/jm049146p

実験手法

X-RAY DIFFRACTION (3 Å)