7NI4

Human ATM kinase domain with bound M4076 inhibitor

Summary for 7NI4

• Entry DOI: 10.2210/pdb7ni4/pdb
• EMDB information: 12343 12345 12346 12347 12350
• Descriptor: Serine-protein kinase ATM, ZINC ION, 8-(1,3-dimethylpyrazol-4-yl)-1-(3-fluoranyl-5-methoxy-pyridin-4-yl)-7-methoxy-3-methyl-imidazo[4,5-c]quinolin-2-one (3 entities in total)
• Functional Keywords: kinase, inhibitor, dna damage response, cancer research, signaling protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 703283.09

Authors

Stakyte, K.,Rotheneder, M. (deposition date: 2021-02-11, release date: 2021-09-01, Last modification date: 2024-07-10)

Primary citation

Stakyte, K.,Rotheneder, M.,Lammens, K.,Bartho, J.D.,Gradler, U.,Fuchss, T.,Pehl, U.,Alt, A.,van de Logt, E.,Hopfner, K.P.
Molecular basis of human ATM kinase inhibition.
Nat.Struct.Mol.Biol., 28:789-798, 2021

PubMed Abstract: 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 ATPγS and to the ATM inhibitors KU-55933 and M4076 at 2.8 Å, 2.8 Å and 3.0 Å 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.

PubMed: 34556870
DOI: 10.1038/s41594-021-00654-x

Experimental method

ELECTRON MICROSCOPY (3 Å)