title: Structures of three classes of anticancer agents bound to the human topoisomerase I-DNA covalent complex.
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.
authors.affiliation: deCODE BioStructures, 7869 NE Day Road West, Bainbridge Island, Washington 98110, USA.
authors.forename: Bart L
authors.initials: BL
authors.lastname: Staker
authors.forename: Michael D
authors.initials: MD
authors.lastname: Feese
authors.forename: Mark
authors.initials: M
authors.lastname: Cushman
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
authors.forename: David
authors.initials: D
authors.lastname: Zembower
authors.forename: Lance
authors.initials: L
authors.lastname: Stewart
authors.forename: Alex B
authors.initials: AB
authors.lastname: Burgin
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D001665:Binding Sites; D002166:Camptothecin / Q000737:chemistry; D002227:Carbazoles / Q000737:chemistry; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry* / Q000235:genetics; D004264:DNA Topoisomerases, Type I / Q000737:chemistry*; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006801:Humans; D007192:Indenes / Q000737:chemistry; D007211:Indoles / Q000737:chemistry; D007364:Intercalating Agents / Q000737:chemistry; D007546:Isoquinolines / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D059004:Topoisomerase I Inhibitors
chemical_list: D000970:Antineoplastic Agents; D002227:Carbazoles; D004791:Enzyme Inhibitors; D007192:Indenes; D007211:Indoles; D007364:Intercalating Agents; D007546:Isoquinolines; D059004:Topoisomerase I Inhibitors; D004247:DNA; D004264:DNA Topoisomerases, Type I; C039109:isoquinoline; D002166:Camptothecin