1seu

Human DNA Topoisomerase I (70 Kda) In Complex With The Indolocarbazole SA315F and Covalent Complex With A 22 Base Pair DNA Duplex

spinqualitylabelsall models 1seu, resolution 3.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 1seu is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3Å Ligands: PTR, SA3, TGP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease TOP1_HUMAN Note=A chromosomal aberration involving TOP1 is found in a form of therapy-related myelodysplastic syndrome. Translocation t(11;20)(p15;q11) with NUP98. Function TOP1_HUMAN Releases the supercoiling and torsional tension of DNA introduced during the DNA replication and transcription by transiently cleaving and rejoining one strand of the DNA duplex. Introduces a single-strand break via transesterification at a target site in duplex DNA. The scissile phosphodiester is attacked by the catalytic tyrosine of the enzyme, resulting in the formation of a DNA-(3'-phosphotyrosyl)-enzyme intermediate and the expulsion of a 5'-OH DNA strand. The free DNA strand then undergoes passage around the unbroken strand thus removing DNA supercoils. Finally, in the religation step, the DNA 5'-OH attacks the covalent intermediate to expel the active-site tyrosine and restore the DNA phosphodiester backbone (By similarity). Regulates the alternative splicing of tissue factor (F3) pre-mRNA in endothelial cells. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed 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. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Topoisomerase 3D structures

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