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

Science. 1998 Mar 6;279(5356):1504-13. doi: 10.1126/science.279.5356.1504.

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

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

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

Substances

  • Antineoplastic Agents, Phytogenic
  • DNA-Binding Proteins
  • HCFC1 protein, human
  • Homeodomain Proteins
  • Host Cell Factor C1
  • Octamer Transcription Factor-1
  • Oligodeoxyribonucleotides
  • POU2F1 protein, human
  • Recombinant Proteins
  • Transcription Factors
  • HP1 integrase
  • Tyrosine
  • DNA
  • Integrases
  • DNA Topoisomerases, Type I
  • Camptothecin