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Instruments / Technical Area	Publication Details	Published	Actions
Krios III-Titan Krios III at Diamond	Cryo-EM structure of nucleotide-bound Tel1ATM unravels the molecular basis of inhibition and structural rationale for disease-associated mutations Luke A. Yates , Rhys M. Williams , Sarem Hailemariam , Rafael Ayala , Peter Burgers , Xiaodong Zhang Structure DOI: 10.1016/j.str.2019.10.012 Diamond Proposal Number(s): [19865] Open Access Show Abstract ▼ Abstract: 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 Tel1 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 Tel1 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.	Nov 2019

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Krios III-Titan Krios III at Diamond

Cryo-EM structure of nucleotide-bound Tel1ATM unravels the molecular basis of inhibition and structural rationale for disease-associated mutations

Luke A. Yates , Rhys M. Williams , Sarem Hailemariam , Rafael Ayala , Peter Burgers , Xiaodong Zhang

Structure

DOI: 10.1016/j.str.2019.10.012

Diamond Proposal Number(s): [19865]