DOI: 10.1126/science.279.5356.1504. Crystal Structures of Human Topoisomerase I in Covalent and Noncovalent Complexes with DNA

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

10.1126/science.279.5356.1504

Crossref journal-article

American Association for the Advancement of Science (AAAS)

Science (221)

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.

Bibliography

Redinbo, M. R., Stewart, L., Kuhn, P., Champoux, J. J., & Hol, W. G. J. (1998). Crystal Structures of Human Topoisomerase I in Covalent and Noncovalent Complexes with DNA. Science, 279(5356), 1504â1513.

Authors 5

Matthew R. Redinbo (first)
Lance Stewart (additional)
Peter Kuhn (additional)
James J. Champoux (additional)
Wim G. J. Hol (additional)

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We thank S. Turley E. Pohl S. Suresh B. Bernstein A. Ævarsson D. Chudzik J. Yeh F. Athappilly F. van den Akker C. Verlinde and many other members of the Biomolecular Structure Center at the University of Washington for technical assistance and intellectual support. We also thank the staffs of the Stanford Synchrotron Radiation Laboratory the Brookhaven National Laboratory the Cornell High Energy Synchrotron Source and the European Synchrotron Radiation Laboratory for their extensive support with data collection. Thanks are also due to A. Burgin for advice on the synthesis of oligonucleotides containing a 5′-bridging phosphorothioate and to DNA Express (Fort Collins CO) for conducting the syntheses. Supported by American Cancer Society grant PF-3905 (L.S.) grant GM49156 from the National Institutes of Health (J.J.C.) by a major equipment grant from the Murdock Charitable Trust to the Biomolecular Structure Center and grant NCI CA65656 from the National Institutes of Health (W.G.J.H.). The Stanford Synchrotron Radiation Laboratory is founded by the Department of Energy (BES OBER) and the NIH (NCRR).

Dates

Type	When
Created	23 years, 1 month ago (July 27, 2002, 5:42 a.m.)
Deposited	1 year, 7 months ago (Jan. 12, 2024, 9:53 p.m.)
Indexed	5 days, 17 hours ago (Aug. 30, 2025, 12:38 p.m.)
Issued	27 years, 5 months ago (March 6, 1998)
Published	27 years, 5 months ago (March 6, 1998)
Published Print	27 years, 5 months ago (March 6, 1998)

Funders 0

None

BibTeX

@article{Redinbo_1998, title={Crystal Structures of Human Topoisomerase I in Covalent and Noncovalent Complexes with DNA}, volume={279}, ISSN={1095-9203}, url={http://dx.doi.org/10.1126/science.279.5356.1504}, DOI={10.1126/science.279.5356.1504}, number={5356}, journal={Science}, publisher={American Association for the Advancement of Science (AAAS)}, author={Redinbo, Matthew R. and Stewart, Lance and Kuhn, Peter and Champoux, James J. and Hol, Wim G. J.}, year={1998}, month=mar, pages={1504–1513} }

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  "abstract": "<jats:p>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\u2013base pair DNA duplexes reveal an enzyme that \u201cclamps\u201d 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\u2013DNA complexes.</jats:p>",
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    {
      "key": "e_1_3_1_10_2",
      "unstructured": "The crystal structures of two proteolytic fragments of topo I have been reported from vaccinia (3) and yeast (2). However these structures represent relatively small (9 and 26 kD respectively) NH 2 -terminal fragments of the enzyme that do not contain active-site residues or bound DNA."
    },
    {
      "key": "e_1_3_1_11_2",
      "doi-asserted-by": "crossref",
      "unstructured": "P. D\u2032Arpa et al. Proc. Natl. Acad. Sci. U.S.A. 85 2543 (1988).",
      "DOI": "10.1073/pnas.85.8.2543"
    },
    {
      "key": "e_1_3_1_12_2",
      "doi-asserted-by": "crossref",
      "first-page": "7593",
      "DOI": "10.1074/jbc.271.13.7593",
      "volume": "271",
      "author": "Stewart L.",
      "year": "1996",
      "unstructured": "Stewart L., Ireton G. C., Parker L. H., Madden K. R., Champoux J. J., J. Biol. Chem. 271, 7593 (1996).",
      "journal-title": "J. Biol. Chem."
    },
    {
      "key": "e_1_3_1_13_2",
      "unstructured": "L. Stewart G. C. Ireton J. J. Champoux ibid. p. 7602."
    },
    {
      "key": "e_1_3_1_14_2",
      "first-page": "12408",
      "volume": "267",
      "author": "Alsner J.",
      "year": "1992",
      "unstructured": "Alsner J., Svejstrup J. Q., Kjeldsen E., Sorensen B. S., Westergaard O., ibid. 267, 12408 (1992).",
      "journal-title": "ibid."
    },
    {
      "key": "e_1_3_1_15_2",
      "doi-asserted-by": "crossref",
      "unstructured": "A. K. Bharti M. O. Olson D. W. Kufe E. H. Rubin ibid. 271 1993 (1996).",
      "DOI": "10.1074/jbc.271.4.1993"
    },
    {
      "key": "e_1_3_1_16_2",
      "first-page": "525",
      "volume": "52",
      "author": "Madden K. R.",
      "year": "1992",
      "unstructured": "Madden K. R., Champoux J. J., Cancer Res. 52, 525 (1992).",
      "journal-title": "Cancer Res."
    },
    {
      "key": "e_1_3_1_17_2",
      "doi-asserted-by": "crossref",
      "first-page": "355",
      "DOI": "10.1006/jmbi.1997.1056",
      "volume": "269",
      "author": "Stewart L.",
      "year": "1997",
      "unstructured": "Stewart L., Ireton G. C., Champoux J. J., J. Mol. Biol. 269, 355 (1997).",
      "journal-title": "J. Mol. Biol."
    },
    {
      "key": "e_1_3_1_18_2",
      "unstructured": "The reconstituted enzyme is more sensitive to ionic strength and more distributive in its mode of action than the full-length enzyme (16 20)."
    },
    {
      "key": "e_1_3_1_19_2",
      "doi-asserted-by": "crossref",
      "first-page": "3097",
      "DOI": "10.1093/nar/12.7.3097",
      "volume": "12",
      "author": "Been M. D.",
      "year": "1984",
      "unstructured": "Been M. D., Burgess R. R., Champoux J. J., Nucleic Acids Res 12, 3097 (1984).",
      "journal-title": "Nucleic Acids Res"
    },
    {
      "key": "e_1_3_1_20_2",
      "first-page": "1543",
      "volume": "13",
      "author": "Andersen A. H.",
      "year": "1985",
      "unstructured": "Andersen A. H., Gocke E., Bonven B. J., Nielsen O. F., Westergaard O., ibid. 13, 1543 (1985).",
      "journal-title": "ibid."
    },
    {
      "key": "e_1_3_1_21_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1126/science.279.5356.1534"
    },
    {
      "key": "e_1_3_1_22_2",
      "doi-asserted-by": "crossref",
      "unstructured": "M. E. Wall et al. J. Am. Chem. 88 3888 (1966);",
      "DOI": "10.1021/ja00968a057"
    },
    {
      "key": "e_1_3_1_22_3",
      "first-page": "632",
      "volume": "7",
      "author": "Horwitz S. B.",
      "year": "1971",
      "unstructured": "Horwitz S. B., Chang C. K., Grollman A. P., Mol. Pharmacol. 7, 632 (1971).",
      "journal-title": "Mol. Pharmacol."
    },
    {
      "key": "e_1_3_1_23_2",
      "doi-asserted-by": "crossref",
      "first-page": "14873",
      "DOI": "10.1016/S0021-9258(17)38654-4",
      "volume": "260",
      "author": "Hsiang Y. H.",
      "year": "1985",
      "unstructured": "Hsiang Y. H., Hertzberg R., Hecht S., Liu L. F., J. Biol. Chem. 260, 14873 (1985).",
      "journal-title": "J. Biol. Chem."
    },
    {
      "key": "e_1_3_1_24_2",
      "first-page": "6318",
      "volume": "49",
      "author": "Bjornsti M. A.",
      "year": "1989",
      "unstructured": "Bjornsti M. A., Benedetti P., Viglianti G. A., Wang J. C., Cancer Res. 49, 6318 (1989).",
      "journal-title": "Cancer Res."
    },
    {
      "key": "e_1_3_1_25_2",
      "doi-asserted-by": "crossref",
      "first-page": "715",
      "DOI": "10.1021/jm00123a038",
      "volume": "32",
      "author": "Hertzberg R. P.",
      "year": "1989",
      "unstructured": "Hertzberg R. P., et al., J. Med. Chem. 32, 715 (1989).",
      "journal-title": "J. Med. Chem."
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    {
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      "doi-asserted-by": "crossref",
      "unstructured": "S. Sawada et al. Chem. Pharmacol. Bull. 39 3183 (1991).",
      "DOI": "10.1248/cpb.39.3183"
    },
    {
      "key": "e_1_3_1_27_2",
      "doi-asserted-by": "crossref",
      "first-page": "8521",
      "DOI": "10.1093/nar/17.21.8521",
      "volume": "17",
      "author": "Porter S. E.",
      "year": "1989",
      "unstructured": "Porter S. E., Champoux J. J., Nucleic Acids Res. 17, 8521 (1989).",
      "journal-title": "Nucleic Acids Res."
    },
    {
      "key": "e_1_3_1_28_2",
      "doi-asserted-by": "crossref",
      "first-page": "4629",
      "DOI": "10.1021/bi00437a018",
      "volume": "28",
      "author": "Hertzberg R. P.",
      "year": "1989",
      "unstructured": "Hertzberg R. P., Caranfa M. J., Hecht S. M., Biochemistry 28, 4629 (1989);",
      "journal-title": "Biochemistry"
    },
    {
      "key": "e_1_3_1_28_3",
      "doi-asserted-by": "crossref",
      "first-page": "669",
      "DOI": "10.1016/0022-2836(91)90503-X",
      "volume": "222",
      "author": "Svejstrup J. Q.",
      "year": "1991",
      "unstructured": "Svejstrup J. Q., Christiansen K., Gromova I. I., Andersen A. H., Westergaard O., J. Mol. Biol. 222, 669 (1991).",
      "journal-title": "J. Mol. Biol."
    },
    {
      "key": "e_1_3_1_29_2",
      "doi-asserted-by": "crossref",
      "first-page": "19287",
      "DOI": "10.1016/S0021-9258(17)30656-7",
      "volume": "265",
      "author": "Hertzberg R. P.",
      "year": "1990",
      "unstructured": "Hertzberg R. P., et al., J. Biol. Chem. 265, 19287 (1990).",
      "journal-title": "J. Biol. Chem."
    },
    {
      "key": "e_1_3_1_30_2",
      "doi-asserted-by": "crossref",
      "first-page": "5613",
      "DOI": "10.1021/bi00475a028",
      "volume": "29",
      "author": "Bendixen C.",
      "year": "1990",
      "unstructured": "Bendixen C., Thomsen B., Alsner J., Westergaard O., Biochemistry 29, 5613 (1990).",
      "journal-title": "Biochemistry"
    },
    {
      "key": "e_1_3_1_31_2",
      "first-page": "5077",
      "volume": "49",
      "author": "Hsiang Y. H.",
      "year": "1989",
      "unstructured": "Hsiang Y. H., Lihou M. G., Liu L. F., Cancer Res. 49, 5077 (1989).",
      "journal-title": "Cancer Res."
    },
    {
      "key": "e_1_3_1_32_2",
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      "author": "Benedetti P.",
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      "unstructured": "Benedetti P., Fiorani P., Capuani L., Wang J. C., ibid. 53, 4343 (1993);",
      "journal-title": "ibid."
    },
    {
      "key": "e_1_3_1_32_3",
      "doi-asserted-by": "crossref",
      "first-page": "22322",
      "DOI": "10.1016/S0021-9258(18)41531-1",
      "volume": "268",
      "author": "Knab A. M.",
      "year": "1993",
      "unstructured": "Knab A. M., Fertala J., Bjornsti M. A., J. Biol. Chem. 268, 22322 (1993);",
      "journal-title": "J. Biol. Chem."
    },
    {
      "key": "e_1_3_1_32_4",
      "first-page": "2433",
      "volume": "269",
      "author": "Rubin E.",
      "year": "1994",
      "unstructured": "Rubin E., et al., ibid. 269, 2433 (1994);",
      "journal-title": "ibid."
    },
    {
      "key": "e_1_3_1_32_5",
      "first-page": "1516",
      "volume": "57",
      "author": "Wang L. F.",
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      "unstructured": "Wang L. F., et al., Cancer Res. 57, 1516 (1997);",
      "journal-title": "Cancer Res."
    },
    {
      "key": "e_1_3_1_32_6",
      "doi-asserted-by": "crossref",
      "first-page": "69",
      "DOI": "10.1093/nar/19.1.69",
      "volume": "19",
      "author": "Tamura H.",
      "year": "1991",
      "unstructured": "Tamura H., et al., Nucleic Acids Res. 19, 69 (1991);",
      "journal-title": "Nucleic Acids Res."
    },
    {
      "key": "e_1_3_1_32_7",
      "doi-asserted-by": "crossref",
      "first-page": "25463",
      "DOI": "10.1016/S0021-9258(19)74414-7",
      "volume": "268",
      "author": "Tanizawa A.",
      "year": "1993",
      "unstructured": "Tanizawa A., et al., J. Biol. Chem. 268, 25463 (1993);",
      "journal-title": "J. Biol. Chem."
    },
    {
      "key": "e_1_3_1_32_8",
      "doi-asserted-by": "crossref",
      "first-page": "571",
      "DOI": "10.1016/0006-291X(92)91094-7",
      "volume": "188",
      "author": "Kubota N.",
      "year": "1992",
      "unstructured": "Kubota N., et al., Biochem. Biophys. Res. Commun. 188, 571 (1992);",
      "journal-title": "Biochem. Biophys. Res. Commun."
    },
    {
      "key": "e_1_3_1_32_9",
      "unstructured": "; X. G. Li et al. Bioch. Pharmacol. 53 1019 (1997)."
    },
    {
      "key": "e_1_3_1_33_2",
      "doi-asserted-by": "crossref",
      "first-page": "28702",
      "DOI": "10.1016/S0021-9258(19)61962-9",
      "volume": "269",
      "author": "Leteurtre F.",
      "year": "1994",
      "unstructured": "Leteurtre F., et al., J. Biol. Chem. 269, 28702 (1994).",
      "journal-title": "J. Biol. Chem."
    },
    {
      "key": "e_1_3_1_34_2",
      "unstructured": "The reconstituted enzyme was prepared by incubating crude nuclear extracts containing the 58-kD core domain (expressed in insect cells) with the immobilized glutathione-S-transferase (GST)\u2013COOH-terminal domain fusion protein (expressed in E. coli ) (16). The reconstituted core plus COOH-terminal enzyme was liberated by factor Xa cleavage. The reconstituted human topo I was separated from factor Xa and any free GST or COOH-terminal domain by POROS SP20 chromatography as described (16). DNA oligonucleotides were synthesized by DNA express (Fort Collins CO) and purified as described (11). Oligonucleotides that contained a 5\u2032-bridging phosphorothioate linkage at the site of topo I cleavage were synthesized according to Burgin et al. (34) where 5\u2032-( S -trityl)-mercapto-5\u2032-deoxythymidine-3\u2032- O -(2-cyanoethyl- N N -diisopropylamino)phosphite was used for the synthesis of the +1 nucleotide in the cleaved strand of the high-affinity topo I binding site from T. thermophilus (19). Duplex oligonucleotides were prepared by mixing equimolar concentrations of complementary strands each at a final concentration of 0.1 mM in the presence of 6 mM NaCl. Annealing of the two strands was achieved by slow cooling from 80\u00b0C to room temperature over a period of 8 hours."
    },
    {
      "key": "e_1_3_1_35_2",
      "doi-asserted-by": "crossref",
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      "DOI": "10.1093/nar/23.15.2973",
      "volume": "23",
      "author": "Burgin A. B.",
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      "unstructured": "Burgin A. B., Huizenga B. N., Nash H. A., Nucleic Acids Res. 23, 2973 (1995).",
      "journal-title": "Nucleic Acids Res."
    },
    {
      "key": "e_1_3_1_36_2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0076-6879(97)76073-7"
    },
    {
      "key": "e_1_3_1_37_2",
      "doi-asserted-by": "crossref",
      "first-page": "231",
      "DOI": "10.1093/nar/25.1.231",
      "volume": "25",
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      "year": "1997",
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      "journal-title": "Nucleic Acids Res."
    },
    {
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      "doi-asserted-by": "crossref",
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      "DOI": "10.1016/0092-8674(94)90231-3",
      "volume": "77",
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      "year": "1994",
      "unstructured": "Klemm J. D., Rould M. A., Aurora R., Herr W., Pabo C., Cell 77, 21 (1994).",
      "journal-title": "Cell"
    },
    {
      "key": "e_1_3_1_39_2",
      "first-page": "227",
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      "author": "Hickman A. B.",
      "year": "1997",
      "unstructured": "Hickman A. B., Waninger S., Scocca J. J., Dyda F., ibid. 89, 227 (1997).",
      "journal-title": "ibid."
    },
    {
      "key": "e_1_3_1_40_2",
      "doi-asserted-by": "crossref",
      "first-page": "3605",
      "DOI": "10.1093/nar/25.18.3605",
      "volume": "25",
      "author": "Esposito D.",
      "year": "1997",
      "unstructured": "Esposito D., Scocca J. J., Nucleic Acids Res. 25, 3605 (1997);",
      "journal-title": "Nucleic Acids Res."
    },
    {
      "key": "e_1_3_1_40_3",
      "unstructured": "; HP1 integrase also uses a transient 3\u2032-phosphate-tyrosine intermediate during its catalytic cycle of integration and excision of the phage DNA and is representative of the family of bacteriophage integrases."
    },
    {
      "key": "e_1_3_1_41_2",
      "first-page": "1465",
      "volume": "49",
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      "year": "1989",
      "unstructured": "Jaxel C., Kohn K. W., Wani M. C., Wall M. E., Pommier Y., Cancer Res. 49, 1465 (1989);",
      "journal-title": "Cancer Res."
    },
    {
      "key": "e_1_3_1_41_3",
      "doi-asserted-by": "crossref",
      "first-page": "7200",
      "DOI": "10.1021/bi00021a035",
      "volume": "34",
      "author": "Tanizawa A.",
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      "unstructured": "Tanizawa A., Kohn K. W., Kohlhagen G., Leteurtre F., Pommier Y., Biochemistry 34, 7200 (1995).",
      "journal-title": "Biochemistry"
    },
    {
      "key": "e_1_3_1_42_2",
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      "DOI": "10.1021/jm00100a022",
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      "author": "Crow R. T.",
      "year": "1992",
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    },
    {
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      "volume": "36",
      "author": "Wall M. E.",
      "year": "1993",
      "unstructured": "Wall M. E., et al., ibid. 36, 2689 (1993).",
      "journal-title": "ibid."
    },
    {
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      "doi-asserted-by": "crossref",
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      "DOI": "10.1021/jm00006a008"
    },
    {
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    },
    {
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      "journal-title": "Nucleic Acids Res."
    },
    {
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    {
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      "DOI": "10.1073/pnas.92.19.8861",
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      "journal-title": "Proc. Natl. Acad. Sci. U.S.A."
    },
    {
      "key": "e_1_3_1_47_2",
      "first-page": "923",
      "author": "McPhail A. T.",
      "year": "1968",
      "unstructured": "McPhail A. T., Sim G. A., J. Chem. Soc. B, 923 (1968).",
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    {
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    },
    {
      "key": "e_1_3_1_49_2",
      "unstructured": "Z. Otwinowski in ibid. pp. 80\u201386."
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    {
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    },
    {
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    {
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      "unstructured": "Jones T. A., Zou J.-Y., Cowan S. W., ibid. A47, 110 (1991).",
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    },
    {
      "key": "e_1_3_1_53_2",
      "doi-asserted-by": "crossref",
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    {
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    },
    {
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      "first-page": "803",
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    {
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      "DOI": "10.1038/355472a0",
      "volume": "355",
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      "year": "1992",
      "unstructured": "___, Nature 355, 472 (1992).",
      "journal-title": "Nature"
    },
    {
      "key": "e_1_3_1_57_2",
      "doi-asserted-by": "publisher",
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      "journal-title": "Biochemistry"
    },
    {
      "key": "e_1_3_1_59_2",
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      "doi-asserted-by": "crossref",
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    {
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    {
      "key": "e_1_3_1_61_2",
      "doi-asserted-by": "publisher",
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      "unstructured": "We thank S. Turley E. Pohl S. Suresh B. Bernstein A. \u00c6varsson D. Chudzik J. Yeh F. Athappilly F. van den Akker C. Verlinde and many other members of the Biomolecular Structure Center at the University of Washington for technical assistance and intellectual support. We also thank the staffs of the Stanford Synchrotron Radiation Laboratory the Brookhaven National Laboratory the Cornell High Energy Synchrotron Source and the European Synchrotron Radiation Laboratory for their extensive support with data collection. Thanks are also due to A. Burgin for advice on the synthesis of oligonucleotides containing a 5\u2032-bridging phosphorothioate and to DNA Express (Fort Collins CO) for conducting the syntheses. Supported by American Cancer Society grant PF-3905 (L.S.) grant GM49156 from the National Institutes of Health (J.J.C.) by a major equipment grant from the Murdock Charitable Trust to the Biomolecular Structure Center and grant NCI CA65656 from the National Institutes of Health (W.G.J.H.). The Stanford Synchrotron Radiation Laboratory is founded by the Department of Energy (BES OBER) and the NIH (NCRR)."
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