Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Antineoplastic Agents, Phytogenic / metabolism
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Antineoplastic Agents, Phytogenic / pharmacology
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Binding Sites
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Camptothecin / analogs & derivatives
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Camptothecin / metabolism
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Camptothecin / pharmacology
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Crystallography, X-Ray
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DNA / chemistry
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DNA / metabolism*
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DNA Topoisomerases, Type I / chemistry*
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DNA Topoisomerases, Type I / genetics
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DNA Topoisomerases, Type I / metabolism
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DNA-Binding Proteins*
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Homeodomain Proteins / chemistry
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Host Cell Factor C1
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Humans
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Hydrogen Bonding
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Integrases / chemistry
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Models, Molecular
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Mutation
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Nucleic Acid Conformation
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Octamer Transcription Factor-1
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Oligodeoxyribonucleotides / chemistry
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Oligodeoxyribonucleotides / metabolism
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Protein Conformation*
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Protein Structure, Secondary
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Recombinant Proteins / chemistry
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Transcription Factors / chemistry
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Tyrosine / chemistry
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Tyrosine / metabolism
Substances
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Antineoplastic Agents, Phytogenic
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DNA-Binding Proteins
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HCFC1 protein, human
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Homeodomain Proteins
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Host Cell Factor C1
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Octamer Transcription Factor-1
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Oligodeoxyribonucleotides
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POU2F1 protein, human
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Recombinant Proteins
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Transcription Factors
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HP1 integrase
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Tyrosine
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DNA
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Integrases
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DNA Topoisomerases, Type I
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Camptothecin