Imperial College London
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ProfessorXiaodongZhang

Faculty of Medicine, Department of Infectious Disease

Professor of Macromolecular Structure and Function
 
 
 
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Contact

 

+44 (0)20 7594 3151xiaodong.zhang Website

 
 
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Assistant

 

Miss Kelly Butler +44 (0)20 7594 2763

 
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Location

 

104Sir Alexander Fleming BuildingSouth Kensington Campus

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Summary

 

Publications

Citation

BibTex format

@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}
}
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RIS format (EndNote, RefMan)

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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