Journal Article

FZJ-2021-06169

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Time-resolved structural analysis of an RNA-cleaving DNA catalyst

Borggräfe, J. ; Victor, J. ; Rosenbach, H. ; Viegas, A. ; Gertzen, C. G. W. ; Wuebben, C. ; Kovacs, H. ; Gopalswamy, M. ; Riesner, D. ; Steger, G. ; Schiemann, O. ; Gohlke, H.FZJ* ; Span, I. ; Etzkorn, M. (Corresponding author)FZJ*

2022
Nature Publ. Group London [u.a.]

This record in other databases:      

Please use a persistent id in citations: http://hdl.handle.net/2128/29837  doi:10.1038/s41586-021-04225-4

Abstract: 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.

---

Contributing Institute(s):

1. Jülich Supercomputing Center (JSC)
2. John von Neumann - Institut für Computing (NIC)
3. Strukturbiochemie (IBI-7)
4. Bioinformatik (IBG-4)

Research Program(s):

1. 5111 - Domain-Specific Simulation & Data Life Cycle Labs (SDLs) and Research Groups (POF4-511) (POF4-511)
2. 2171 - Biological and environmental resources for sustainable use (POF4-217) (POF4-217)
3. 2172 - Utilization of renewable carbon and energy sources and engineering of ecosystem functions (POF4-217) (POF4-217)
4. 5244 - Information Processing in Neuronal Networks (POF4-524) (POF4-524)
5. Forschergruppe Gohlke (hkf7_20200501) (hkf7_20200501)

Appears in the scientific report 2022

---

Database coverage:
; ; BIOSIS Previews ; Biological Abstracts ; Chemical Reactions ; Clarivate Analytics Master Journal List ; Current Contents - Agriculture, Biology and Environmental Sciences ; Current Contents - Life Sciences ; Current Contents - Physical, Chemical and Earth Sciences ; Ebsco Academic Search ; Essential Science Indicators ; Index Chemicus ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection ; Zoological Record

---