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- PDB-6s8f: Structure of nucleotide-bound Tel1/ATM -

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Basic information

Entry
Database: PDB / ID: 6s8f
TitleStructure of nucleotide-bound Tel1/ATM
ComponentsSerine/threonine-protein kinase TEL1,Serine/threonine-protein kinase TEL1,Serine/threonine-protein kinase TEL1,Serine/threonine-protein kinase TEL1,Serine/threonine-protein kinase TEL1
KeywordsHYDROLASE / Kinase / DNA Damage Response / CryoEM / Phosphatidylinositol-3-kinase-like kinase
Function / homology
Function and homology information


Pexophagy / DNA Damage/Telomere Stress Induced Senescence / Sensing of DNA Double Strand Breaks / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / telomeric DNA binding / signal transduction in response to DNA damage / negative regulation of TORC1 signaling / telomere maintenance / DNA damage checkpoint signaling / double-strand break repair ...Pexophagy / DNA Damage/Telomere Stress Induced Senescence / Sensing of DNA Double Strand Breaks / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / telomeric DNA binding / signal transduction in response to DNA damage / negative regulation of TORC1 signaling / telomere maintenance / DNA damage checkpoint signaling / double-strand break repair / chromatin organization / chromosome, telomeric region / non-specific serine/threonine protein kinase / protein kinase activity / phosphorylation / DNA repair / protein serine kinase activity / protein serine/threonine kinase activity / DNA damage response / mitochondrion / ATP binding / nucleus
Similarity search - Function
Telomere-length maintenance and DNA damage repair / Serine/threonine-protein kinase ATM, plant / ATM, catalytic domain / Telomere-length maintenance and DNA damage repair / Telomere-length maintenance and DNA damage repair / FATC domain / FATC / FATC domain / PIK-related kinase / FAT domain profile. ...Telomere-length maintenance and DNA damage repair / Serine/threonine-protein kinase ATM, plant / ATM, catalytic domain / Telomere-length maintenance and DNA damage repair / Telomere-length maintenance and DNA damage repair / FATC domain / FATC / FATC domain / PIK-related kinase / FAT domain profile. / FATC domain profile. / Phosphatidylinositol 3- and 4-kinases signature 1. / Phosphatidylinositol 3/4-kinase, conserved site / Phosphatidylinositol 3- and 4-kinases signature 2. / Phosphatidylinositol 3-/4-kinase, catalytic domain superfamily / Phosphoinositide 3-kinase, catalytic domain / Phosphatidylinositol 3- and 4-kinase / Phosphatidylinositol 3- and 4-kinases catalytic domain profile. / Phosphatidylinositol 3-/4-kinase, catalytic domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / Serine/threonine-protein kinase TEL1
Similarity search - Component
Biological speciesSaccharomyces cerevisiae (brewer's yeast)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4 Å
AuthorsYates, L.A. / Williams, R.M. / Ayala, R. / Zhang, X.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Wellcome Trust United Kingdom
CitationJournal: Structure / Year: 2020
Title: Cryo-EM Structure of Nucleotide-Bound Tel1 Unravels the Molecular Basis of Inhibition and Structural Rationale for Disease-Associated Mutations.
Authors: Luke A Yates / Rhys M Williams / Sarem Hailemariam / Rafael Ayala / Peter Burgers / Xiaodong Zhang /
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- ...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.
History
DepositionJul 9, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 30, 2019Provider: repository / Type: Initial release
Revision 1.1Dec 4, 2019Group: Database references / Category: citation
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Jan 15, 2020Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year

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Structure visualization

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Assembly

Deposited unit
F: 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
H: 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)586,2206
Polymers585,1592
Non-polymers1,0614
Water0
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area8170 Å2
ΔGint-80 kcal/mol
Surface area249920 Å2

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Components

#1: Protein 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 / ATM homolog / DNA-damage checkpoint kinase TEL1 / Telomere length regulation protein 1


Mass: 292579.406 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Saccharomyces cerevisiae (brewer's yeast)
Gene: TEL1, YBL088C, YBL0706 / Production host: Saccharomyces cerevisiae (brewer's yeast)
References: UniProt: P38110, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-ANP / PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER


Mass: 506.196 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H17N6O12P3 / Comment: AMP-PNP, energy-carrying molecule analogue*YM
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
Has ligand of interestN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Tel1/ATM / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Saccharomyces cerevisiae (brewer's yeast)
Source (recombinant)Organism: Saccharomyces cerevisiae (brewer's yeast)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy
Image recordingElectron dose: 88.8 e/Å2 / Film or detector model: FEI FALCON III (4k x 4k)

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Processing

EM software
IDNameVersionCategory
4GctfCTF correction
10RELION3initial Euler assignment
11RELION3final Euler assignment
12RELION3classification
13RELION33D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 167596 / Symmetry type: POINT

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