The 8-17 DNAzyme can operate in a single active structure regardless of metal ion cofactor

Julia Wieruszewska, Aleksandra Pawłowicz, Ewa Połomska, Karol Pasternak, Zofia Gdaniec and Witold Andrałojć ()
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Julia Wieruszewska: Polish Academy of Sciences, 61-704
Aleksandra Pawłowicz: Polish Academy of Sciences, 61-704
Ewa Połomska: Polish Academy of Sciences, 61-704
Karol Pasternak: Polish Academy of Sciences, 61-704
Zofia Gdaniec: Polish Academy of Sciences, 61-704
Witold Andrałojć: Polish Academy of Sciences, 61-704

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract DNAzymes – synthetic enzymes made of DNA — have long attracted attention as RNA-targeting therapeutic agents. Yet, as of now, no DNAzyme-based drug has been approved, partially due to our lacking understanding of their molecular mode of action. In this work we report the solution structure of 8–17 DNAzyme bound to a Zn2+ ion solved through NMR spectroscopy. Surprisingly, it turned out to be very similar to the previously solved Pb2+-bound form (catalytic domain RMSD = 1.28 Å), despite a long-standing literature consensus that Pb2+ recruits a different DNAzyme fold than other metal ion cofactors. Our follow-up NMR investigations in the presence of other ions — Mg2+, Na+, and Pb2+ – suggest that at DNAzyme concentrations used in NMR all these ions induce a similar tertiary fold. Based on these findings, we propose a model for 8–17 DNAzyme interactions with metal ions postulating the existence of only a single catalytically-active structure, yet populated to a different extent depending on the metal ion cofactor. Our results provide structural information on the 8-17 DNAzyme in presence of non-Pb2+ cofactors, including the biologically relevant Mg2+ ion.

Date: 2024
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DOI: 10.1038/s41467-024-48638-x

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