Crystal structures of human topoisomerase I in covalent and noncovalent complexes with DNA.
Topoisomerases I promote the relaxation of DNA superhelical tension by introducing a transient single-stranded break in duplex DNA and are vital for the processes of replication, transcription, and recombination. The crystal structures at 2.1 and 2.5 angstrom resolution of reconstituted human topoisomerase I comprising the core and carboxyl-terminal domains in covalent and noncovalent complexes with 22-base pair DNA duplexes reveal an enzyme that "clamps" around essentially B-form DNA. The core domain and the first eight residues of the carboxyl-terminal domain of the enzyme, including the active-site nucleophile tyrosine-723, share significant structural similarity with the bacteriophage family of DNA integrases. A binding mode for the anticancer drug camptothecin is proposed on the basis of chemical and biochemical information combined with these three-dimensional structures of topoisomerase I-DNA complexes.
Redinbo
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MR
Biomolecular Structure Center and Department of Biological Structure, Box 357742, School of Medicine, University of Washington, Seattle, WA 98195, USA.
Stewart
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Kuhn
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Champoux
J J
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Hol
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WG
D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D002166:Camptothecin / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D004264:DNA Topoisomerases, Type I / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins / Q000737:chemistry; D051863:Host Cell Factor C1; D006801:Humans; D006860:Hydrogen Bonding; D019426:Integrases / Q000737:chemistry; D008958:Models, Molecular; D009154:Mutation; D009690:Nucleic Acid Conformation; D050811:Octamer Transcription Factor-1; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry; D014157:Transcription Factors / Q000737:chemistry; D014443:Tyrosine / Q000737:chemistry / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D004268:DNA-Binding Proteins; C497692:HCFC1 protein, human; D018398:Homeodomain Proteins; D051863:Host Cell Factor C1; D050811:Octamer Transcription Factor-1; D009838:Oligodeoxyribonucleotides; C494165:POU2F1 protein, human; D011994:Recombinant Proteins; D014157:Transcription Factors; C060509:HP1 integrase; D014443:Tyrosine; D004247:DNA; D019426:Integrases; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin