DNAzymes are DNA molecules capable of catalyzing chemical reactions, such as site specific RNA cleavage, which makes them potentially powerful therapeutic tools. However, limited activity in cellular conditions in which divalent metal ions – essential cofactors of most DNAzymes – are scarce, as well as our lacking understanding of their molecular modes of action have thus far hindered the realization of the therapeutic promise of DNAzymes.

Acquiring a deep structural understanding of DNAzyme catalytic activity could provide a way forward for the field, yet as of now structures of only two RNA-cleaving DNAzymes have been determined and moreover for the archetypical 8-17 DNAzyme literature data acquired to date suggested the existence of two different catalytically proficient folds selected based of the type of M²⁺ cofactor being present. Researchers from IBCh PAS led by dr Witold Andrałojć (Julia Wieruszewska, mgr Aleksandra Pawłowicz, mgr Ewa Połomska, dr Karol Pasternak i prof. dr hab. Zofia Gdaniec) have determined the 3D structure of 8-17 DNAzyme in presence of Zn²⁺ and demonstrated that contrary to previous conclusions this enzyme has only a single active fold, yet present in a structural equilibrium with inactive states which is strongly influenced by the type of the cofactor being present. The improved understanding of structural aspects of DNAzyme 8-17 action opens an opportunity for rational design of its improved variants more active in cellular conditions.

Publication link: https://www.nature.com/articles/s41467-024-48638-x