Crystal structures of human topoisomerase I in covalent and noncovalent complexes with DNA
Crystal structures of human topoisomerase I in covalent and noncovalent complexes with DNA
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DOI：
10.1126/science.279.5356.1504
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发表时间：
1998-03-06
期刊：
影响因子：
56.9
通讯作者：
Hol, WGJ
中科院分区：
文献类型：
--
作者：
Redinbo, MR;Stewart, L;Hol, WGJ
拓扑异构酶I通过在双链DNA中引入瞬时单链断裂来促进DNA超螺旋张力的松弛，并且对于复制、转录和重组过程至关重要，重构的人拓扑异构酶I在2.1和2.5埃分辨率下的晶体结构，所述重构的人拓扑异构酶I包含与22-羟基-N-甲基-N-碱基对DNA双链体揭示了一种酶，其“夹”在基本上B型DNA周围。该酶的核心结构域和羧基末端结构域的前8个残基，包括活性位点亲核体酪氨酸-723，与DNA整合酶的噬菌体家族共享显著的结构相似性。根据化学和生化信息，结合拓扑异构酶I-DNA复合物的三维结构，提出了抗癌药物喜树碱的结合模式。
Topoisomerases I promote the relaxation of DNA superhelical tension by introducing a transient Single-stranded break in duplex DNA and are vital for the processes of replication, transcription, and recombination, The crystal structures at 2.1 and 2.5 angstrom resolution of reconstituted human topoisomerase I comprising the core and carboxyl-terminal domains in covalent and noncovalent complexes with 22-base pair DNA duplexes reveal an enzyme that "clamps" around essentially B-form DNA, The core domain and the first eight residues of the carboxyl-terminal domain of the enzyme, including the active-site nuleophile tyrosine-723, share significant structural similarity with the bacteriophage family of DNA integrases. A binding mode for the anticancer drug camptothecin is proposed on the basis of chemical and biochemical information combined with these three-dimensional structures of topoisomerase I-DNA complexes.