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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 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. Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.

Citation

Luke A Yates, Rhys M Williams, Sarem Hailemariam, Rafael Ayala, Peter Burgers, Xiaodong Zhang. Cryo-EM Structure of Nucleotide-Bound Tel1ATM Unravels the Molecular Basis of Inhibition and Structural Rationale for Disease-Associated Mutations. Structure (London, England : 1993). 2020 Jan 07;28(1):96-104.e3

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PMID: 31740029

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