Structures of Three Classes of Anticancer Agents Bound to the Human Topoisomerase I−DNA Covalent Complex

Citations Over TimeTop 10% of 2005 papers

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.

Related Papers

• Protein-linked DNA strand breaks induced in mammalian cells by camptothecin, an inhibitor of topoisomerase I.(1989)
• → Inhibition of Topoisomerase I Function by Coralyne and 5,6-Dihydrocoralyne(1996)55 cited
• → Development of a stable camptothecin-resistant subline of P388 leukemia with reduced topoisomerase I content.(1990)127 cited
• → On the role of E-ring oxygen atoms in the binding of camptothecin to the topoisomerase I–DNA covalent binary complex(2004)14 cited
• → Human TopoisomeraseIInhibitors(2016)