结构的三个类抗癌药物绑定到人类拓扑异构酶I-DNA共价复杂。
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Cushman股份提单,Feese MD, M,英国移民Y, Zembower D, L·斯图尔特,Burgin AB
结构的三个类抗癌药物绑定到人类拓扑异构酶I-DNA共价复杂。
J地中海化学。2005年4月7日,48 (7):2336 - 45。
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15801827 (在PubMed]
- 文摘
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人类的拓扑异构酶I (top1)是一组不同的抗癌的分子目标化合物,包括喜树碱,indolocarbazoles, indenoisoquinolines。这些化合物绑定到一个瞬态top1-DNA共价复杂和抑制酶的重新填缝着一长串的尼克创建来缓解在双螺旋DNA超螺旋张力。(Hertzberg, r p;et al ., 1989, 28岁,4629 - 4638。黄懿慧香;et al .生物。化学1985,260,14873 - 14878。Champoux说道,j。j物质。启。2001,70,369 - 413。斯图尔特,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.