In this section
@article{Yates:2019:10.1101/696203,
author = {Yates, LA and Williams, RM and Hailemariam, S and Ayala, R and Burgers, P and Zhang, X},
doi = {10.1101/696203},
title = {Structure of nucleotide-bound Tel1<sup>ATM</sup> reveals the molecular basis of inhibition and structural rationale for disease mutations},
url = {http://dx.doi.org/10.1101/696203},
year = {2019}
}
TY - JOUR
AB - <jats:sec><jats:title>SUMMARY</jats:title><jats:p>Yeast Tel1 and its highly conserved human orthologue 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 cryo electron 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 PIKK-regulatory domain-Insert (PRD-I) 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.</jats:p></jats:sec>
AU - Yates,LA
AU - Williams,RM
AU - Hailemariam,S
AU - Ayala,R
AU - Burgers,P
AU - Zhang,X
DO - 10.1101/696203
PY - 2019///
TI - Structure of nucleotide-bound Tel1<sup>ATM</sup> reveals the molecular basis of inhibition and structural rationale for disease mutations
UR - http://dx.doi.org/10.1101/696203
ER -
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