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Crystal structures of human topoisomerase i in covalent and noncovalent complexes with DNA

Academic Article
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Overview

authors

  • Redinbo, M. R.
  • Stewart, L.
  • Kuhn, Peter
  • Champoux, J. J.
  • Hol, W. G. J.

publication date

  • March 1998

journal

  • Science  Journal

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.

subject areas

  • Antineoplastic Agents, Phytogenic
  • Binding Sites
  • Camptothecin
  • Crystallography, X-Ray
  • DNA
  • DNA Topoisomerases, Type I
  • DNA-Binding Proteins
  • Homeodomain Proteins
  • Host Cell Factor C1
  • Humans
  • Hydrogen Bonding
  • Integrases
  • Models, Molecular
  • Mutation
  • Nucleic Acid Conformation
  • Octamer Transcription Factor-1
  • Oligodeoxyribonucleotides
  • Protein Conformation
  • Protein Structure, Secondary
  • Recombinant Proteins
  • Transcription Factors
  • Tyrosine
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Identity

International Standard Serial Number (ISSN)

  • 0036-8075

Digital Object Identifier (DOI)

  • 10.1126/science.279.5356.1504

PubMed ID

  • 9488644
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Additional Document Info

start page

  • 1504

end page

  • 1513

volume

  • 279

issue

  • 5356

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