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- PDB-6caj: Electron cryo-microscopy of the eukaryotic translation initiation... -

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Basic information

Entry
Database: PDB / ID: 6caj
TitleElectron cryo-microscopy of the eukaryotic translation initiation factor 2B from Homo sapiens
Components(Translation initiation factor eIF-2B subunit ...) x 5
KeywordsTRANSLATION / guanine nucleotide exchange factor / translation initiation / ISRIB-bound / decameric complex
Function / homology
Function and homology information


eukaryotic translation initiation factor 2B complex / Recycling of eIF2:GDP / cytoplasmic translational initiation / guanyl-nucleotide exchange factor complex / oligodendrocyte development / astrocyte development / astrocyte differentiation / regulation of translational initiation / positive regulation of translational initiation / response to glucose ...eukaryotic translation initiation factor 2B complex / Recycling of eIF2:GDP / cytoplasmic translational initiation / guanyl-nucleotide exchange factor complex / oligodendrocyte development / astrocyte development / astrocyte differentiation / regulation of translational initiation / positive regulation of translational initiation / response to glucose / ovarian follicle development / translation initiation factor binding / response to endoplasmic reticulum stress / myelination / translation initiation factor activity / guanyl-nucleotide exchange factor activity / hippocampus development / central nervous system development / translational initiation / response to peptide hormone / regulation of translation / T cell receptor signaling pathway / response to heat / positive regulation of apoptotic process / GTP binding / ATP binding / identical protein binding / membrane / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Translation initiation factor eIF-2B subunit alpha, N-terminal / : / : / Translation initiation factor eIF-2B subunit epsilon, N-terminal / Translation initiation factor eIF-2B subunit epsilon, W2 domain / : / : / Initiation factor 2B-related / Initiation factor 2B-like, C-terminal / Initiation factor 2 subunit family ...Translation initiation factor eIF-2B subunit alpha, N-terminal / : / : / Translation initiation factor eIF-2B subunit epsilon, N-terminal / Translation initiation factor eIF-2B subunit epsilon, W2 domain / : / : / Initiation factor 2B-related / Initiation factor 2B-like, C-terminal / Initiation factor 2 subunit family / eIF4-gamma/eIF5/eIF2-epsilon / Domain at the C-termini of GCD6, eIF-2B epsilon, eIF-4 gamma and eIF-5 / W2 domain / W2 domain profile. / Nucleotidyl transferase domain / Nucleotidyl transferase / NagB/RpiA transferase-like / Bacterial transferase hexapeptide (six repeats) / Trimeric LpxA-like superfamily / Nucleotide-diphospho-sugar transferases / Armadillo-type fold
Similarity search - Domain/homology
Chem-C7B / Translation initiation factor eIF2B subunit beta / Translation initiation factor eIF2B subunit epsilon / Translation initiation factor eIF2B subunit alpha / Translation initiation factor eIF2B subunit gamma / Translation initiation factor eIF2B subunit delta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.8 Å
AuthorsTsai, J.C. / Miller-Vedam, L.E. / Anand, A.A. / Jaishankar, P. / Nguyen, H.C. / Renslo, A.R. / Frost, A. / Walter, P.
Funding support United States, 2items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI)Faculty Scholar 55108523 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)1DP2GM110772-01 United States
CitationJournal: Science / Year: 2018
Title: Structure of the nucleotide exchange factor eIF2B reveals mechanism of memory-enhancing molecule.
Authors: Jordan C Tsai / Lakshmi E Miller-Vedam / Aditya A Anand / Priyadarshini Jaishankar / Henry C Nguyen / Adam R Renslo / Adam Frost / Peter Walter /
Abstract: Regulation by the integrated stress response (ISR) converges on the phosphorylation of translation initiation factor eIF2 in response to a variety of stresses. Phosphorylation converts eIF2 from a ...Regulation by the integrated stress response (ISR) converges on the phosphorylation of translation initiation factor eIF2 in response to a variety of stresses. Phosphorylation converts eIF2 from a substrate to a competitive inhibitor of its dedicated guanine nucleotide exchange factor, eIF2B, thereby inhibiting translation. ISRIB, a drug-like eIF2B activator, reverses the effects of eIF2 phosphorylation, and in rodents it enhances cognition and corrects cognitive deficits after brain injury. To determine its mechanism of action, we solved an atomic-resolution structure of ISRIB bound in a deep cleft within decameric human eIF2B by cryo-electron microscopy. Formation of fully active, decameric eIF2B holoenzyme depended on the assembly of two identical tetrameric subcomplexes, and ISRIB promoted this step by cross-bridging a central symmetry interface. Thus, regulation of eIF2B assembly emerges as a rheostat for eIF2B activity that tunes translation during the ISR and that can be further modulated by ISRIB.
History
DepositionJan 31, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 11, 2018Provider: repository / Type: Initial release
Revision 1.1Feb 20, 2019Group: Author supporting evidence / Data collection / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.2Nov 20, 2019Group: Author supporting evidence / Database references / Structure summary
Category: chem_comp / pdbx_audit_support / struct_ref_seq_dif
Item: _chem_comp.pdbx_synonyms / _pdbx_audit_support.funding_organization / _struct_ref_seq_dif.details

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Structure visualization

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Assembly

Deposited unit
B: Translation initiation factor eIF-2B subunit epsilon
J: Translation initiation factor eIF-2B subunit gamma
H: Translation initiation factor eIF-2B subunit alpha
C: Translation initiation factor eIF-2B subunit beta
F: Translation initiation factor eIF-2B subunit delta
A: Translation initiation factor eIF-2B subunit epsilon
I: Translation initiation factor eIF-2B subunit gamma
G: Translation initiation factor eIF-2B subunit alpha
D: Translation initiation factor eIF-2B subunit beta
E: Translation initiation factor eIF-2B subunit delta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)526,77111
Polymers526,31910
Non-polymers4511
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration, immunoprecipitation, equilibrium centrifugation
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area31990 Å2
ΔGint-153 kcal/mol
Surface area122790 Å2

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Components

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Translation initiation factor eIF-2B subunit ... , 5 types, 10 molecules BAJIHGCDFE

#1: Protein Translation initiation factor eIF-2B subunit epsilon / eIF-2B GDP-GTP exchange factor subunit epsilon


Mass: 80452.586 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EIF2B5, EIF2BE / Production host: Escherichia coli (E. coli) / References: UniProt: Q13144
#2: Protein Translation initiation factor eIF-2B subunit gamma / eIF-2B GDP-GTP exchange factor subunit gamma


Mass: 50304.230 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EIF2B3 / Production host: Escherichia coli (E. coli) / References: UniProt: Q9NR50
#3: Protein Translation initiation factor eIF-2B subunit alpha / eIF-2B GDP-GTP exchange factor subunit alpha


Mass: 33754.148 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EIF2B1, EIF2BA / Production host: Escherichia coli (E. coli) / References: UniProt: Q14232
#4: Protein Translation initiation factor eIF-2B subunit beta / S20I15 / S20III15 / eIF-2B GDP-GTP exchange factor subunit beta


Mass: 41008.578 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EIF2B2, EIF2BB / Production host: Escherichia coli (E. coli) / References: UniProt: P49770
#5: Protein Translation initiation factor eIF-2B subunit delta / eIF-2B GDP-GTP exchange factor subunit delta


Mass: 57640.168 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EIF2B4, EIF2BD / Production host: Escherichia coli (E. coli) / References: UniProt: Q9UI10

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Non-polymers , 1 types, 1 molecules

#6: Chemical ChemComp-C7B / 2-(4-chloranylphenoxy)-~{N}-[4-[2-(4-chloranylphenoxy)ethanoylamino]cyclohexyl]ethanamide / ISRIB


Mass: 451.343 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H24Cl2N2O4 / Comment: inhibitor*YM

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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: Translation initiation factor eIF-2B decamer / Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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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 FIELD
Image recordingElectron dose: 1.63 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

EM software
IDNameVersionCategory
1Gautomatch0.55particle selection
2SerialEMimage acquisition
4Gctf1.06CTF correction
7UCSF Chimeramodel fitting
9RELION2initial Euler assignment
10FREALIGNfinal Euler assignment
12FREALIGN3D reconstruction
13PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 202125
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 2.8 Å / Resolution method: FSC 0.5 CUT-OFF / Num. of particles: 202125 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL

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