Congratulations to Leonardo Serafim, first author, and to group alumnus Brad Kossmann on our new preprint on bioRxiv entitled “Orchestrated metal ion repositioning defines the dynamic catalytic strategy of the essential DNA repair nuclease APE1”, a collaboration with John Tainer, Susan Tsutakawa, Sankar Mitra and David Wilson III.
Human AP-endonuclease 1 (APE1) is a central enzyme of base excision repair: it cuts DNA at abasic sites, among the most common lesions in the genome. How it achieves high specificity and efficient catalysis with a single metal ion has been unclear. We report a high-resolution structure of the APE1–DNA Michaelis complex with its physiological Mg2+ cofactor. Combining this structure with molecular dynamics and metadynamics simulations, we uncovered a “moving metal ion” mechanism: the Mg2+ ion repositions in a coordinated way to trigger a concerted reaction, without forming a pentavalent intermediate.
A previously unrecognized hydrogen-bonding network couples activation of the catalytic water to the movement of the metal ion, two events that occur on opposite sides of the active site. The findings show how enzymes synchronize distant active-site rearrangements with the transition state, and provide a foundation for designing inhibitors of APE1, which is overexpressed in cancer.
Serafim, L. F., Tsutakawa, S. E., Arvai, A. S., Kossmann, B. R., Mantha, A. K., Abbotts, R., Wilson III, D. M., Mitra, S., Tainer, J. A. & Ivanov, I.* bioRxiv 2026.05.11.724140.
