Structural Flexibility in Human Topoisomerase I Revealed in Multiple Non-isomorphous Crystal Structures

拓扑异构酶 结晶学 连接器 立体化学 晶体结构 DNA 单斜晶系 化学 分子 生物物理学 生物 生物化学 计算机科学 操作系统 有机化学
作者
Matthew R. Redinbo,Lance Stewart,James J. Champoux,Wim G. J. Hól
出处
期刊:Journal of Molecular Biology [Elsevier BV]
卷期号:292 (3): 685-696 被引量:79
标识
DOI:10.1006/jmbi.1999.3065
摘要

Human topoisomerase I plays a critical role in chromosomal stability by relaxing the DNA superhelical tension that arises from a variety of nuclear processes, including replication, transcription, and chromatin remodeling. Human topoisomerase I is a ∼91 kDa enzyme composed of four major domains: a 24 kDa N-terminal domain,a56 kDa core domain,a7 kDa linker domain, anda6 kDa C-terminal domain containing the active-site Tyr723 residue. A monoclinic crystal structure of a 70 kDa N-terminally truncated form of human topoisomerase I in non-covalent complex with a 22 bp DNA duplex exhibited remarkable crystal-to-crystal non-isomorphism; shifts in cell constants of up to 9 Å in the b -axis length and up to 8.5 ° in the β-angle were observed. Eight crystal structures of human topoisomerase I - DNA complexes from this crystal form were determined to between 2.8 and 3.25 Å resolution. These structures revealed both dramatic shifts in crystal packing and functionally suggestive regions of conformational flexibility in the structure of the enzyme. Crystal packing shifts of up to 20.5 Å combined with rotations of up to 11.5 ° were observed, helping to explain the variability in cell constants. When the core subdomain III regions of the eight structures are superimposed, the “cap” (core subdomains I and II) of the molecule is observed to rotate by up to 4.6 ° and to shift by up to 3.6 Å. The linker domain shows the greatest degree of conformational flexibility, rotating and shifting by up to 2.5 ° and 4.6 Å, respectively, in five of eight structures, and becoming disordered altogether in the remaining three. These observed regions of conformational flexibility in the cap and the linker domain are consistent with the structural flexibility invoked in the “controled rotation” mechanism proposed for the relaxation of DNA superhelical tension by human topoisomerase I.
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