Long-range allosteric restraint by the Spiral-Pincer scaffold gates oxidative activation of the ATM kinase

Spiral–Pincer gates oxidative activation of the ATM kinase by restricting an oxidation-competent dimer conformation that is rarely populated in the resting state.

• Why it matters: ATM activation by oxidative stress requires disulfide formation at Cys2991, but how the distant Spiral–Pincer scaffold controls access to the PRD-release state is unclear.
• What they did: Using an AlphaFold3-completed full-length ATM dimer model plus well-tempered metadynamics, they mapped conformational landscapes and compared intact versus Spiral–Pincer–removed constructs.
• The result: Removing Spiral–Pincer makes the oxidation-competent conformation dominant and narrows the landscape to a few states, with asymmetric PRD loop rearrangements driven by domain contacts rather than direct access to reactive cysteines.

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