Journal
STRUCTURE
Volume 28, Issue 1, Pages 96-+Publisher
CELL PRESS
DOI: 10.1016/j.str.2019.10.012
Keywords
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Funding
- Wellcome Trust [210658/Z/18/Z]
- MRC
- BBSRC
- NIH [GM118129]
- NSF [2014157291]
- Wellcome Trust [210658/Z/18/Z] Funding Source: Wellcome Trust
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Yeast Tel1 and its highly conserved human ortholog ataxia-telangiectasia mutated (ATM) are large protein kinases central to the maintenance of genome integrity. Mutations in ATM are found in ataxia-telangiectasia (A-T) patients and ATM is one of the most frequently mutated genes in many cancers. Using cryoelectron microscopy, we present the structure of Tell in a nucleotide-bound state. Our structure reveals molecular details of key residues surrounding the nucleotide binding site and provides a structural and molecular basis for its intrinsically low basal activity. We show that the catalytic residues are in a productive conformation for catalysis, but the phosphatidylinositol 3-kinase-related kinase (PIKK) regulatory domain insert restricts peptide substrate access and the N-lobe is in an open conformation, thus explaining the requirement for Tell activation. Structural comparisons with other PIKKs suggest a conserved and common allosteric activation mechanism. Our work also provides a structural rationale for many mutations found in A-T and cancer.
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