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Structures of three classes of anticancer agents bound to the human topoisomerase I-DNA covalent complex.
J Med Chem. 2005 Apr 07; 48(7):2336-45.JM

Abstract

Human topoisomerase I (top1) is the molecular target of a diverse set of anticancer compounds, including the camptothecins, indolocarbazoles, and indenoisoquinolines. These compounds bind to a transient top1-DNA covalent complex and inhibit the resealing of a single-strand nick that the enzyme creates to relieve superhelical tension in duplex DNA. (Hertzberg, R. P.; et al. Biochem. 1989, 28, 4629-4638. Hsiang, Y. H.; et al. J. Biol. Chem 1985, 260, 14873-14878. Champoux, J. J. Annu. Rev. Biochem. 2001, 70, 369-413. Stewart, L.; et al. Science 1998, 729, 1534-1541.) We report the X-ray crystal structures of the human top1-DNA complex bound with camptothecin and representative members of the indenoisoquinoline and indolocarbazole classes of top1 poisons. The planar nature of all three structurally diverse classes allows them to intercalate between DNA base pairs at the site of single-strand cleavage. All three classes of compounds have a free electron pair near Arg364, a residue that if mutated confers resistance to all three classes of drugs. The common intercalative binding mode is augmented by unexpected chemotype-specific contacts with amino acid residues Asn352 and Glu356, which adopt alternative side-chain conformations to accommodate the bound compounds. These new X-ray structures explain how very different molecules can stabilize top1-DNA covalent complexes and will aid the rational design of completely novel structural classes of anticancer drugs.

Authors+Show Affiliations

deCODE BioStructures, 7869 NE Day Road West, Bainbridge Island, Washington 98110, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

15801827

Citation

Staker, Bart L., et al. "Structures of Three Classes of Anticancer Agents Bound to the Human Topoisomerase I-DNA Covalent Complex." Journal of Medicinal Chemistry, vol. 48, no. 7, 2005, pp. 2336-45.
Staker BL, Feese MD, Cushman M, et al. Structures of three classes of anticancer agents bound to the human topoisomerase I-DNA covalent complex. J Med Chem. 2005;48(7):2336-45.
Staker, B. L., Feese, M. D., Cushman, M., Pommier, Y., Zembower, D., Stewart, L., & Burgin, A. B. (2005). Structures of three classes of anticancer agents bound to the human topoisomerase I-DNA covalent complex. Journal of Medicinal Chemistry, 48(7), 2336-45.
Staker BL, et al. Structures of Three Classes of Anticancer Agents Bound to the Human Topoisomerase I-DNA Covalent Complex. J Med Chem. 2005 Apr 7;48(7):2336-45. PubMed PMID: 15801827.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Structures of three classes of anticancer agents bound to the human topoisomerase I-DNA covalent complex. AU - Staker,Bart L, AU - Feese,Michael D, AU - Cushman,Mark, AU - Pommier,Yves, AU - Zembower,David, AU - Stewart,Lance, AU - Burgin,Alex B, PY - 2005/4/2/pubmed PY - 2005/5/6/medline PY - 2005/4/2/entrez SP - 2336 EP - 45 JF - Journal of medicinal chemistry JO - J Med Chem VL - 48 IS - 7 N2 - Human topoisomerase I (top1) is the molecular target of a diverse set of anticancer compounds, including the camptothecins, indolocarbazoles, and indenoisoquinolines. These compounds bind to a transient top1-DNA covalent complex and inhibit the resealing of a single-strand nick that the enzyme creates to relieve superhelical tension in duplex DNA. (Hertzberg, R. P.; et al. Biochem. 1989, 28, 4629-4638. Hsiang, Y. H.; et al. J. Biol. Chem 1985, 260, 14873-14878. Champoux, J. J. Annu. Rev. Biochem. 2001, 70, 369-413. Stewart, L.; et al. Science 1998, 729, 1534-1541.) We report the X-ray crystal structures of the human top1-DNA complex bound with camptothecin and representative members of the indenoisoquinoline and indolocarbazole classes of top1 poisons. The planar nature of all three structurally diverse classes allows them to intercalate between DNA base pairs at the site of single-strand cleavage. All three classes of compounds have a free electron pair near Arg364, a residue that if mutated confers resistance to all three classes of drugs. The common intercalative binding mode is augmented by unexpected chemotype-specific contacts with amino acid residues Asn352 and Glu356, which adopt alternative side-chain conformations to accommodate the bound compounds. These new X-ray structures explain how very different molecules can stabilize top1-DNA covalent complexes and will aid the rational design of completely novel structural classes of anticancer drugs. SN - 0022-2623 UR - https://www.unboundmedicine.com/medline/citation/15801827/Structures_of_three_classes_of_anticancer_agents_bound_to_the_human_topoisomerase_I_DNA_covalent_complex_ L2 - https://doi.org/10.1021/jm049146p DB - PRIME DP - Unbound Medicine ER -