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Science 6 March 1998:
Vol. 279. no. 5356, pp. 1504 - 1513
DOI: 10.1126/science.279.5356.1504
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Research Articles

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

Matthew R. Redinbo, * Lance Stewart, *dagger Peter Kuhn, James J. Champoux, Wim G. J. Hol ddagger

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.

M. R. Redinbo and L. Stewart are at the Biomolecular Structure Center and Department of Biological Structure, Box 357742, School of Medicine, University of Washington, Seattle, WA 98195, USA. P. Kuhn is at Stanford Synchrotron Radiation Laboratory, Stanford University, Stanford, CA 94309, USA. J. J. Champoux is in the Department of Microbiology, Box 357242, School of Medicine, University of Washington, Seattle, WA 98915, USA. W. G. J. Hol is in the Departments of Biological Structure and Biochemistry, Howard Hughes Medical Institute and Biomolecular Structure Center, Box 357742, School of Medicine, University of Washington, Seattle, WA 98195, USA.
*   These authors contributed equally to this work.

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

ddagger    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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Cancer Res. 61, 1964-1969
   Abstract »    Full Text »
Use of Camptothecin-resistant Mammalian Cell Lines to Evaluate the Role of Topoisomerase I in the Antiproliferative Activity of the Indolocarbazole, NB-506, and Its Topoisomerase I Binding Site.
Y. Urasaki, G. Laco, Y. Takebayashi, C. Bailly, G. Kohlhagen, and Y. Pommier (2001)
Cancer Res. 61, 504-508
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Interaction of human DNA topoisomerase I wi