title: A novel norindenoisoquinoline structure reveals a common interfacial inhibitor paradigm for ternary trapping of the topoisomerase I-DNA covalent complex.
abstract: We show that five topoisomerase I inhibitors (two indenoisoquinolines, two camptothecins, and one indolocarbazole) each intercalate between the base pairs flanking the cleavage site generated during the topoisomerase I catalytic cycle and are further stabilized by a network of hydrogen bonds with topoisomerase I. The interfacial inhibition paradigm described for topoisomerase I inhibitors can be generalized to a variety of natural products that trap macromolecular complexes as they undergo catalytic conformational changes that create hotspots for drug binding. Stabilization of such conformational states results in uncompetitive inhibition and exemplifies the relevance of screening for ligands and drugs that stabilize ("trap") these macromolecular complexes.
authors.affiliation: Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Building 37, Room 5068, Bethesda, MD 20892-4255, USA.
authors.forename: Christophe
authors.initials: C
authors.lastname: Marchand
authors.forename: Smitha
authors.initials: S
authors.lastname: Antony
authors.forename: Kurt W
authors.initials: KW
authors.lastname: Kohn
authors.forename: Mark
authors.initials: M
authors.lastname: Cushman
authors.forename: Alexandra
authors.initials: A
authors.lastname: Ioanoviciu
authors.forename: Bart L
authors.initials: BL
authors.lastname: Staker
authors.forename: Alex B
authors.initials: AB
authors.lastname: Burgin
authors.forename: Lance
authors.initials: L
authors.lastname: Stewart
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
mesh_terms: D002166:Camptothecin / Q000737:chemistry / Q000494:pharmacology; D003461:Crystallography; D004247:DNA / Q000737:chemistry; D004249:DNA Damage; D004264:DNA Topoisomerases, Type I / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D006860:Hydrogen Bonding; D007192:Indenes / Q000737:chemistry* / Q000494:pharmacology*; D007546:Isoquinolines / Q000737:chemistry* / Q000494:pharmacology*; D015394:Molecular Structure; D059004:Topoisomerase I Inhibitors; D019772:Topotecan / Q000737:chemistry / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D007192:Indenes; D007546:Isoquinolines; D059004:Topoisomerase I Inhibitors; C510007:norindenoisoquinoline; D019772:Topotecan; D004247:DNA; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin