Molecular basis of human ATM kinase inhibition

Stakyte, K.; Rotheneder, M.; Lammens, K.; Bartho, J. D.; Grädler, U.; Fuchß, T.; Pehl, U.; Alt, A.; Logt, E. van de und Hopfner, K. P. (2021): Molecular basis of human ATM kinase inhibition. In: Nature Structural & Molecular Biology, Bd. 28, Nr. 10: 789-

Abstract

High-resolution cryo-EM structures of human ATM bound to ATP gamma S and two distinct ATM inhibitors provide insights into the mechanism of inhibitor selectivity and offer a framework for structure-based drug design. Human checkpoint kinase ataxia telangiectasia-mutated (ATM) plays a key role in initiation of the DNA damage response following DNA double-strand breaks. ATM inhibition is a promising approach in cancer therapy, but, so far, detailed insights into the binding modes of known ATM inhibitors have been hampered due to the lack of high-resolution ATM structures. Using cryo-EM, we have 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. We determined the structure of the kinase domain bound to ATP gamma S and to the ATM inhibitors KU-55933 and M4076 at 2.8 angstrom, 2.8 angstrom and 3.0 angstrom resolution, respectively. The mode of action and selectivity of the ATM inhibitors can be explained by structural comparison and provide a framework for structure-based drug design.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Chemie und Pharmazie > Department Biochemie
• Themengebiete: 500 Naturwissenschaften und Mathematik > 540 Chemie
• ISSN: 1545-9993
• Sprache: Englisch