6S8F

Structure of nucleotide-bound Tel1/ATM

Summary for 6S8F

• Entry DOI: 10.2210/pdb6s8f/pdb
• EMDB information: 10120
• Descriptor: Serine/threonine-protein kinase TEL1,Serine/threonine-protein kinase TEL1,Serine/threonine-protein kinase TEL1,Serine/threonine-protein kinase TEL1,Serine/threonine-protein kinase TEL1, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, MAGNESIUM ION (3 entities in total)
• Functional Keywords: kinase, dna damage response, cryoem, phosphatidylinositol-3-kinase-like kinase, hydrolase
• Biological source: Saccharomyces cerevisiae (Baker's yeast); More
• Total number of polymer chains: 2
• Total formula weight: 586219.81

Authors

Yates, L.A.,Williams, R.M.,Ayala, R.,Zhang, X. (deposition date: 2019-07-09, release date: 2019-10-30, Last modification date: 2024-05-22)

Primary citation

Yates, L.A.,Williams, R.M.,Hailemariam, S.,Ayala, R.,Burgers, P.,Zhang, X.
Cryo-EM Structure of Nucleotide-Bound Tel1ATMUnravels the Molecular Basis of Inhibition and Structural Rationale for Disease-Associated Mutations.
Structure, 28:96-104.e3, 2020

PubMed 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.

PubMed: 31740029
DOI: 10.1016/j.str.2019.10.012

Experimental method

ELECTRON MICROSCOPY (4 Å)