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-Structure paper
Title | Structural insights into the activation of ataxia-telangiectasia mutated by oxidative stress. |
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Journal, issue, pages | Sci Adv, Vol. 9, Issue 39, Page eadi8291, Year 2023 |
Publish date | Sep 29, 2023 |
Authors | Anna C Howes / Olga Perisic / Roger L Williams / |
PubMed Abstract | Ataxia-telangiectasia mutated (ATM) is a master kinase regulating DNA damage response that is activated by DNA double-strand breaks. However, ATM is also directly activated by reactive oxygen ...Ataxia-telangiectasia mutated (ATM) is a master kinase regulating DNA damage response that is activated by DNA double-strand breaks. However, ATM is also directly activated by reactive oxygen species, but how oxidative activation is achieved remains unknown. We determined the cryo-EM structure of an HO-activated ATM and showed that under oxidizing conditions, ATM formed an intramolecular disulfide bridge between two protomers that are rotated relative to each other when compared to the basal state. This rotation is accompanied by release of the substrate-blocking PRD region and twisting of the N-lobe relative to the C-lobe, which greatly optimizes catalysis. This active site remodeling enabled us to capture a substrate (p53) bound to the enzyme. This provides the first structural insights into how ATM is activated during oxidative stress. |
External links | Sci Adv / PubMed:37756394 / PubMed Central |
Methods | EM (single particle) |
Resolution | 2.5 - 3.3 Å |
Structure data | EMDB-17265, PDB-8oxm: EMDB-17266, PDB-8oxo: EMDB-17267, PDB-8oxp: EMDB-17268, PDB-8oxq: |
Chemicals | ChemComp-ANP: ChemComp-MG: ChemComp-ZN: |
Source |
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Keywords | SIGNALING PROTEIN / Ataxia-Telangiectasia Mutated / ATM / kinase / oxidative stress / p53 |