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000904599 1001_ $$0P:(DE-Juel1)168267$$aBorggräfe, Jan$$b0
000904599 245__ $$aTime-resolved structural analysis of an RNA-cleaving DNA catalyst
000904599 260__ $$aLondon [u.a.]$$bNature Publ. Group$$c2022
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000904599 520__ $$aThe 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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000904599 7001_ $$0P:(DE-Juel1)176160$$aVictor, Julian$$b1
000904599 7001_ $$0P:(DE-HGF)0$$aRosenbach, Hannah$$b2
000904599 7001_ $$0P:(DE-Juel1)161140$$aViegas, Aldino$$b3
000904599 7001_ $$0P:(DE-HGF)0$$aGertzen, Christoph G. W.$$b4
000904599 7001_ $$00000-0002-7860-3149$$aWuebben, Christine$$b5
000904599 7001_ $$00000-0002-5246-9439$$aKovacs, Helena$$b6
000904599 7001_ $$0P:(DE-HGF)0$$aGopalswamy, Mohanraj$$b7
000904599 7001_ $$0P:(DE-HGF)0$$aRiesner, Detlev$$b8
000904599 7001_ $$0P:(DE-HGF)0$$aSteger, Gerhard$$b9
000904599 7001_ $$00000-0001-6346-9779$$aSchiemann, Olav$$b10
000904599 7001_ $$0P:(DE-Juel1)172663$$aGohlke, Holger$$b11
000904599 7001_ $$0P:(DE-HGF)0$$aSpan, Ingrid$$b12
000904599 7001_ $$0P:(DE-Juel1)156341$$aEtzkorn, Manuel$$b13$$eCorresponding author
000904599 773__ $$0PERI:(DE-600)1413423-8$$a10.1038/s41586-021-04225-4$$p144-149$$tNature <London>$$v601$$x0028-0836$$y2022
000904599 8564_ $$uhttps://juser.fz-juelich.de/record/904599/files/Borggraefe_etal_manuscript_read2.pdf$$yPublished on 2021-12-23. Available in OpenAccess from 2022-06-23.
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