A novel norindenoisoquinoline structure reveals a common interfacial inhibitor paradigm for ternary trapping of the topoisomerase I-DNA covalent complex.
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.
Marchand
Christophe
C
Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Building 37, Room 5068, Bethesda, MD 20892-4255, USA.
Antony
Smitha
S
Kohn
Kurt W
KW
Cushman
Mark
M
Ioanoviciu
Alexandra
A
Staker
Bart L
BL
Burgin
Alex B
AB
Stewart
Lance
L
Pommier
Yves
Y
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
D004791:Enzyme Inhibitors; D007192:Indenes; D007546:Isoquinolines; D059004:Topoisomerase I Inhibitors; C510007:norindenoisoquinoline; D019772:Topotecan; D004247:DNA; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin