期刊
NUCLEIC ACIDS RESEARCH
卷 40, 期 18, 页码 9369-9378出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gks668
关键词
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资金
- International Cooperative Research Project (ICORP)
- Japan Science and Technology Agency (JST)
- Takeda Science Foundation
- New Energy and Industrial Technology Development Organization [NEDO] [09A02021a]
- Japan Society for the Promotion of Science [22-6449]
- Grants-in-Aid for Scientific Research [23681042] Funding Source: KAKEN
The three-dimensional (3D) structures of many biomacromolecules have been solved to reveal the functions of these molecules. However, these 3D structures have rarely been applied to constructing efficient molecular devices that function in living cells. Here, we demonstrate a 3D structure-based molecular design principle for constructing short hairpin RNA (shRNA)-mediated genetic information converters; these converters respond to specific proteins and trigger the desired gene expression by modulating the function of the RNA-processing enzyme Dicer. The inhibitory effect on Dicer cleavage against the shRNA designed to specifically bind to U1A spliceosomal protein was correlated with the degree of steric hindrance between Dicer and the shRNA-protein complex in vitro: The level of the hindrance was predicted based on the models. Moreover, the regulation of gene expression was achieved by using the shRNA converters designed to bind to the target U1A or nuclear factor-kappa B (NF-kappa B) p50 proteins expressed in human cells. The 3D molecular design approach is widely applicable for developing new devices in synthetic biology.
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