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Updated: Oct 19, 2025

Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays
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Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays

Published on: October 23, 2019

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Molecular basis of human ATM kinase inhibition

K Stakyte1, M Rotheneder1, K Lammens2

  • 1Gene Center, Department of Biochemistry, Ludwig-Maximilians-Universität, Munich, Germany.

Nature Structural & Molecular Biology
|September 24, 2021
PubMed

Insights

Researchers determined the high-resolution structure of human ataxia telangiectasia-mutated (ATM) kinase, revealing novel zinc-binding motifs and providing insights into ATM inhibitor binding for cancer therapy development.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Cancer Research

Background:

  • The ataxia telangiectasia-mutated (ATM) kinase is crucial for DNA double-strand break repair.
  • ATM inhibition is a targeted cancer therapy strategy.
  • Lack of high-resolution ATM structures has limited understanding of inhibitor binding modes.

Purpose of the Study:

  • To determine the high-resolution structure of human ATM.
  • To elucidate the binding mechanisms of ATM inhibitors.
  • To provide a structural basis for designing novel ATM-targeted cancer drugs.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) was employed to determine ATM structures.
  • Structures were resolved for ATM kinase domain bound to ATPγS, KU-55933, and M4076.
  • High-resolution structural analysis enabled atomic model building.

Main Results:

  • Near-complete atomic model of human ATM was achieved.
  • Two previously unknown zinc-binding motifs within ATM were identified.
  • Structural details of KU-55933 and M4076 binding to ATM were elucidated at 2.8-3.0 Å resolution.

Conclusions:

  • The determined ATM structures explain inhibitor action and selectivity.
  • These findings offer a framework for structure-based design of improved ATM inhibitors.
  • This research advances the development of ATM-targeted cancer therapies.

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