+Open data
-Basic information
Entry | Database: PDB / ID: 7kmf | ||||||
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Title | Sugar phosphate activation of the stress sensor eIF2B | ||||||
Components | (Translation initiation factor eIF-2B subunit ...) x 5 | ||||||
Keywords | TRANSLATION / Translation initiation factor eif-2b | ||||||
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 / central nervous system development / hippocampus 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 | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.91 Å | ||||||
Authors | Nocek, B. / Hao, Q. / Wong, Y. / Stoll, V. / Sidrauski, C. | ||||||
Citation | Journal: Nat Commun / Year: 2021 Title: Sugar phosphate activation of the stress sensor eIF2B. Authors: Qi Hao / Jin-Mi Heo / Boguslaw P Nocek / Kevin G Hicks / Vincent S Stoll / Clint Remarcik / Sean Hackett / Lauren LeBon / Rinku Jain / Dan Eaton / Jared Rutter / Yao Liang Wong / Carmela Sidrauski / Abstract: The multi-subunit translation initiation factor eIF2B is a control node for protein synthesis. eIF2B activity is canonically modulated through stress-responsive phosphorylation of its substrate eIF2. ...The multi-subunit translation initiation factor eIF2B is a control node for protein synthesis. eIF2B activity is canonically modulated through stress-responsive phosphorylation of its substrate eIF2. The eIF2B regulatory subcomplex is evolutionarily related to sugar-metabolizing enzymes, but the biological relevance of this relationship was unknown. To identify natural ligands that might regulate eIF2B, we conduct unbiased binding- and activity-based screens followed by structural studies. We find that sugar phosphates occupy the ancestral catalytic site in the eIF2Bα subunit, promote eIF2B holoenzyme formation and enhance enzymatic activity towards eIF2. A mutant in the eIF2Bα ligand pocket that causes Vanishing White Matter disease fails to engage and is not stimulated by sugar phosphates. These data underscore the importance of allosteric metabolite modulation for proper eIF2B function. We propose that eIF2B evolved to couple nutrient status via sugar phosphate sensing with the rate of protein synthesis, one of the most energetically costly cellular processes. | ||||||
History |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | Molecule: MolmilJmol/JSmol |
-Downloads & links
-Download
PDBx/mmCIF format | 7kmf.cif.gz | 545.5 KB | Display | PDBx/mmCIF format |
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PDB format | pdb7kmf.ent.gz | 429.4 KB | Display | PDB format |
PDBx/mmJSON format | 7kmf.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 7kmf_validation.pdf.gz | 1.3 MB | Display | wwPDB validaton report |
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Full document | 7kmf_full_validation.pdf.gz | 1.4 MB | Display | |
Data in XML | 7kmf_validation.xml.gz | 87.3 KB | Display | |
Data in CIF | 7kmf_validation.cif.gz | 132 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/km/7kmf ftp://data.pdbj.org/pub/pdb/validation_reports/km/7kmf | HTTPS FTP |
-Related structure data
Related structure data | 22924MC 7kmaC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
-Translation initiation factor eIF-2B subunit ... , 5 types, 10 molecules CDFEHGBIJK
#1: Protein | Mass: 41049.633 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 #2: Protein | 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 #3: Protein | Mass: 40552.938 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Details: F6P / Source: (gene. exp.) Homo sapiens (human) / Gene: EIF2B1, EIF2BA / Production host: Escherichia coli (E. coli) / References: UniProt: Q14232 #4: Protein | Mass: 80466.609 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 #5: Protein | 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 |
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-Sugars / Non-polymers , 2 types, 20 molecules
#6: Sugar | #7: Water | ChemComp-HOH / | |
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-Details
Has ligand of interest | Y |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: Tranlation initiation factor eif-2B / Type: COMPLEX / Entity ID: #1-#2, #5-#6 / Source: RECOMBINANT |
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Molecular weight | Experimental value: NO |
Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Escherichia coli (E. coli) |
Buffer solution | pH: 7.5 Details: Prior to grid preparation, the protein mixture was diluted with 25 mM HEPES, 100 mM KCl, 2 mM 446 MgCl2, 1 mM DTT, pH 7.5 to |
Specimen | Conc.: 0.32 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES Details: eif2a was mixed with eif2bcde in 1.5 :1 molar ratio and incubated on ice. |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: TFS KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: OTHER |
Image recording | Electron dose: 44.33 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of real images: 6073 |
-Processing
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EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
Symmetry | Point symmetry: C2 (2 fold cyclic) | ||||||||||||||||||||||||
3D reconstruction | Resolution: 2.91 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 73704 / Symmetry type: POINT | ||||||||||||||||||||||||
Atomic model building | Protocol: RIGID BODY FIT / Details: Real space refinement | ||||||||||||||||||||||||
Atomic model building | PDB-ID: 6CAJ | ||||||||||||||||||||||||
Refinement | Cross valid method: NONE Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2 | ||||||||||||||||||||||||
Displacement parameters | Biso mean: 103.98 Å2 | ||||||||||||||||||||||||
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