1sc7
Human DNA Topoisomerase I (70 Kda) In Complex With The Indenoisoquinoline MJ-II-38 and Covalent Complex With A 22 Base Pair DNA Duplex
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OverviewOverview
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.
DiseaseDisease
Known disease associated with this structure: DNA topoisomerase I, camptothecin-resistant OMIM:[126420]
About this StructureAbout this Structure
1SC7 is a Single protein structure of sequence from Homo sapiens with M38 and PG4 as ligands. Active as DNA topoisomerase, with EC number 5.99.1.2 Full crystallographic information is available from OCA.
ReferenceReference
Structures of three classes of anticancer agents bound to the human topoisomerase I-DNA covalent complex., Staker BL, Feese MD, Cushman M, Pommier Y, Zembower D, Stewart L, Burgin AB, J Med Chem. 2005 Apr 7;48(7):2336-45. PMID:15801827
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