Research Article

Crystal Structures of Human Topoisomerase I in Covalent and Noncovalent Complexes with DNA

Science  06 Mar 1998:
Vol. 279, Issue 5356, pp. 1504-1513
DOI: 10.1126/science.279.5356.1504

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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.

  • * These authors contributed equally to this work.

  • Present address: Emerald BioStructures, 7865 Northeast Day Road West, Bainbridge Island, WA 98110, USA. E-mail: emerald_biostructures{at}rocketmail.com

  • To whom correspondence should be addressed at Biomolecular Structure Center, School of Medicine, University of Washington, Seattle, WA 98195, USA. E-mail: hol{at}gouda.bmsc.washington.edu

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