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

Summary for 1SC7

• Entry DOI: 10.2210/pdb1sc7/pdb
• Related: 1K4S 1K4T
• Descriptor: 5'-D(*AP*AP*AP*AP*AP*GP*AP*CP*TP*T)-3', 5'-D(*(TGP)P*GP*AP*AP*AP*AP*AP*TP*TP*TP*TP*T)-3', 5'-D(*AP*AP*AP*AP*AP*TP*TP*TP*TP*TP*CP*CP*AP*AP*GP*TP*CP*TP*TP*TP*TP*T)-3', ... (6 entities in total)
• Functional Keywords: complex (isomerase-dna), dna, topoisomerase i, drug, poison, idenoisoquinoline, isomerase-dna complex, isomerase/dna
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus, nucleolus: P11387
• Total number of polymer chains: 4
• Total formula weight: 84243.52

Authors

Staker, B.L.,Feese, M.D.,Cushman, M.,Pommier, Y.,Zembower, D.,Stewart, L.,Burgin, A.B. (deposition date: 2004-02-11, release date: 2005-04-19, Last modification date: 2011-07-13)

Primary citation

Staker, B.L.,Feese, M.D.,Cushman, M.,Pommier, Y.,Zembower, D.,Stewart, L.,Burgin, A.B.
Structures of three classes of anticancer agents bound to the human topoisomerase I-DNA covalent complex
J.Med.Chem., 48:2336-2345, 2005

PubMed 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.

PubMed: 15801827
DOI: 10.1021/jm049146p

Experimental method

X-RAY DIFFRACTION (3 Å)