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Title | Molecular basis of human ATM kinase inhibition. |
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Journal, issue, pages | Nat Struct Mol Biol, Vol. 28, Issue 10, Page 789-798, Year 2021 |
Publish date | Sep 23, 2021 |
![]() | K Stakyte / M Rotheneder / K Lammens / J D Bartho / U Grädler / T Fuchß / U Pehl / A Alt / E van de Logt / K P Hopfner / ![]() |
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 ...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. |
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Methods | EM (single particle) |
Resolution | 2.78 - 3.34 Å |
Structure data | ![]() EMDB-12343: ![]() EMDB-12345: ![]() EMDB-12346: ![]() EMDB-12347: EMDB-12350, PDB-7ni4: EMDB-12351: Human ATM kinase with bound inhibitor KU-55933 (composite structure) EMDB-12352, PDB-7ni6: |
Chemicals | ![]() ChemComp-ZN: ![]() ChemComp-UGK: ![]() ChemComp-UF8: ![]() ChemComp-AGS: ![]() ChemComp-MG: |
Source |
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![]() | SIGNALING PROTEIN / Kinase / inhibitor / DNA damage response / cancer research |