Karl-Peter Hopfner and his group in collaboration with Merck KGgaA determined high-resolution structures of inhibitor-bound human ATM kinase. The researchers explained the mode of action and selectivity of potential anti-cancer drug-candidates by structural comparison and provided the framework for structure-based drug design.
Human checkpoint kinase ATM plays a key role in the initiation of the DNA damage response following DNA double strand breaks. ATM inhibition is a promising approach in cancer therapy, unfortunately, detailed insights into the binding modes of known ATM inhibitors were so far hampered due to the lack of high-resolution ATM structures. Using cryo-electron microscopy Stakyte, et al. determined the structure of human ATM to an overall resolution sufficient to build a near complete atomic model and identify two hitherto unknown zinc-binding motifs. For the first time, they determined the structure of the kinase domain bound to ATPgS and ATM inhibitors KU-55933 and M4076 at 2.8 Å resolution or higher.
Molecular basis of human ATM kinase inhibition
Stakyte K, Rotheneder M, Lammens K, Bartho JD, Grädler U, Fuchß T, Pehl U, Alt A, van de Logt E and Hopfner KP.
Nature Structural and Molecular Biology, Sept 23, 2021 https://doi.org/10.1038/s41594-021-00654-x