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001     904599
005     20230123110547.0
024 7 _ |2 doi
|a 10.1038/s41586-021-04225-4
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|a 0028-0836
024 7 _ |2 ISSN
|a 1476-4687
024 7 _ |2 Handle
|a 2128/29837
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|a altmetric:119630050
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|a pmid:34949858
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037 _ _ |a FZJ-2021-06169
082 _ _ |a 500
100 1 _ |0 P:(DE-Juel1)168267
|a Borggräfe, Jan
|b 0
245 _ _ |a Time-resolved structural analysis of an RNA-cleaving DNA catalyst
260 _ _ |a London [u.a.]
|b Nature Publ. Group
|c 2022
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520 _ _ |a The 10–23 DNAzyme is one of the most prominent catalytically active DNA sequences1,2. Its ability to cleave a wide range of RNA targets with high selectivity entails a substantial therapeutic and biotechnological potential2. However, the high expectations have not yet been met, a fact that coincides with the lack of high-resolution and time-resolved information about its mode of action3. Here we provide high-resolution NMR characterization of all apparent states of the prototypic 10–23 DNAzyme and present a comprehensive survey of the kinetics and dynamics of its catalytic function. The determined structure and identified metal-ion-binding sites of the precatalytic DNAzyme–RNA complex reveal that the basis of the DNA-mediated catalysis is an interplay among three factors: an unexpected, yet exciting molecular architecture; distinct conformational plasticity; and dynamic modulation by metal ions. We further identify previously hidden rate-limiting transient intermediate states in the DNA-mediated catalytic process via real-time NMR measurements. Using a rationally selected single-atom replacement, we could considerably enhance the performance of the DNAzyme, demonstrating that the acquired knowledge of the molecular structure, its plasticity and the occurrence of long-lived intermediate states constitutes a valuable starting point for the rational design of next-generation DNAzymes.
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|a Victor, Julian
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|a Rosenbach, Hannah
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700 1 _ |0 P:(DE-Juel1)161140
|a Viegas, Aldino
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|a Gertzen, Christoph G. W.
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700 1 _ |0 0000-0002-7860-3149
|a Wuebben, Christine
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|a Kovacs, Helena
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|a Gopalswamy, Mohanraj
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|a Etzkorn, Manuel
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|e Corresponding author
773 _ _ |0 PERI:(DE-600)1413423-8
|a 10.1038/s41586-021-04225-4
|p 144-149
|t Nature
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|y 2022
856 4 _ |u https://juser.fz-juelich.de/record/904599/files/Borggraefe_etal_manuscript_read2.pdf
|y Published on 2021-12-23. Available in OpenAccess from 2022-06-23.
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