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- EMDB-22924: Sugar phosphate activation of the stress sensor eIF2B -

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Basic information

Entry
Database: EMDB / ID: EMD-22924
TitleSugar phosphate activation of the stress sensor eIF2B
Map data
Sample
  • Complex: Tranlation initiation factor eif-2B
    • Protein or peptide: Translation initiation factor eIF-2B subunit beta
    • Protein or peptide: Translation initiation factor eIF-2B subunit delta
    • Protein or peptide: Translation initiation factor eIF-2B subunit gamma
    • Ligand: 6-O-phosphono-beta-D-fructofuranose
  • Protein or peptide: Translation initiation factor eIF-2B subunit alpha
  • Protein or peptide: Translation initiation factor eIF-2B subunit epsilon
  • Ligand: water
Function / homology
Function and homology information


eukaryotic translation initiation factor 2B complex / Recycling of eIF2:GDP / cytoplasmic translational initiation / oligodendrocyte development / guanyl-nucleotide exchange factor complex / 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 / oligodendrocyte development / guanyl-nucleotide exchange factor complex / astrocyte development / astrocyte differentiation / regulation of translational initiation / positive regulation of translational initiation / response to glucose / ovarian follicle development / translation initiation factor binding / translational initiation / translation initiation factor activity / myelination / response to endoplasmic reticulum stress / guanyl-nucleotide exchange factor activity / central nervous system development / hippocampus development / 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 / cytoplasm / cytosol
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 / 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. ...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 / Trimeric LpxA-like superfamily / Nucleotide-diphospho-sugar transferases / Armadillo-type fold
Similarity search - Domain/homology
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)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.91 Å
AuthorsNocek B / Hao Q / Wong Y / Stoll V / Sidrauski C
CitationJournal: 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
DepositionNov 2, 2020-
Header (metadata) releaseJul 14, 2021-
Map releaseJul 14, 2021-
UpdateJul 14, 2021-
Current statusJul 14, 2021Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.4534
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.4534
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7kmf
  • Surface level: 0.4534
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_22924.png

Downloads & links

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Map

FileDownload / File: emd_22924.map.gz / Format: CCP4 / Size: 149.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.04 Å
Density
Contour LevelBy AUTHOR: 0.4534 / Movie #1: 0.4534
Minimum - Maximum-1.6513569 - 2.4321759
Average (Standard dev.)0.00089202553 (±0.055801585)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions340340340
Spacing340340340
CellA=B=C: 353.59998 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.041.041.04
M x/y/z340340340
origin x/y/z0.0000.0000.000
length x/y/z353.600353.600353.600
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ300300300
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS340340340
D min/max/mean-1.6512.4320.001

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Supplemental data

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Half map: #1

Fileemd_22924_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_22924_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Tranlation initiation factor eif-2B

EntireName: Tranlation initiation factor eif-2B
Components
  • Complex: Tranlation initiation factor eif-2B
    • Protein or peptide: Translation initiation factor eIF-2B subunit beta
    • Protein or peptide: Translation initiation factor eIF-2B subunit delta
    • Protein or peptide: Translation initiation factor eIF-2B subunit gamma
    • Ligand: 6-O-phosphono-beta-D-fructofuranose
  • Protein or peptide: Translation initiation factor eIF-2B subunit alpha
  • Protein or peptide: Translation initiation factor eIF-2B subunit epsilon
  • Ligand: water

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Supramolecule #1: Tranlation initiation factor eif-2B

SupramoleculeName: Tranlation initiation factor eif-2B / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2, #5-#6
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Escherichia coli (E. coli)

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Macromolecule #1: Translation initiation factor eIF-2B subunit beta

MacromoleculeName: Translation initiation factor eIF-2B subunit beta / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 41.049633 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MDYKDDDDKE NLYFQSMPGS AAKGSELSER IESFVETLKR GGGPRSSEEM ARETLGLLRQ IITDHRWSNA GELMELIRRE GRRMTAAQP SETTVGNMVR RVLKIIREEY GRLHGRSDES DQQESLHKLL TSGGLNEDFS FHYAQLQSNI IEAINELLVE L EGTMENIA ...String:
MDYKDDDDKE NLYFQSMPGS AAKGSELSER IESFVETLKR GGGPRSSEEM ARETLGLLRQ IITDHRWSNA GELMELIRRE GRRMTAAQP SETTVGNMVR RVLKIIREEY GRLHGRSDES DQQESLHKLL TSGGLNEDFS FHYAQLQSNI IEAINELLVE L EGTMENIA AQALEHIHSN EVIMTIGFSR TVEAFLKEAA RKRKFHVIVA ECAPFCQGHE MAVNLSKAGI ETTVMTDAAI FA VMSRVNK VIIGTKTILA NGALRAVTGT HTLALAAKHH STPLIVCAPM FKLSPQFPNE EDSFHKFVAP EEVLPFTEGD ILE KVSVHC PVFDYVPPEL ITLFISNIGG NAPSYIYRLM SELYHPDDHV L

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Macromolecule #2: Translation initiation factor eIF-2B subunit delta

MacromoleculeName: Translation initiation factor eIF-2B subunit delta / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 57.640168 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MAAVAVAVRE DSGSGMKAEL PPGPGAVGRE MTKEEKLQLR KEKKQQKKKR KEEKGAEPET GSAVSAAQCQ VGPTRELPES GIQLGTPRE KVPAGRSKAE LRAERRAKQE AERALKQARK GEQGGPPPKA SPSTAGETPS GVKRLPEYPQ VDDLLLRRLV K KPERQQVP ...String:
MAAVAVAVRE DSGSGMKAEL PPGPGAVGRE MTKEEKLQLR KEKKQQKKKR KEEKGAEPET GSAVSAAQCQ VGPTRELPES GIQLGTPRE KVPAGRSKAE LRAERRAKQE AERALKQARK GEQGGPPPKA SPSTAGETPS GVKRLPEYPQ VDDLLLRRLV K KPERQQVP TRKDYGSKVS LFSHLPQYSR QNSLTQFMSI PSSVIHPAMV RLGLQYSQGL VSGSNARCIA LLRALQQVIQ DY TTPPNEE LSRDLVNKLK PYMSFLTQCR PLSASMHNAI KFLNKEITSV GSSKREEEAK SELRAAIDRY VQEKIVLAAQ AIS RFAYQK ISNGDVILVY GCSSLVSRIL QEAWTEGRRF RVVVVDSRPW LEGRHTLRSL VHAGVPASYL LIPAASYVLP EVSK VLLGA HALLANGSVM SRVGTAQLAL VARAHNVPVL VCCETYKFCE RVQTDAFVSN ELDDPDDLQC KRGEHVALAN WQNHA SLRL LNLVYDVTPP ELVDLVITEL GMIPCSSVPV VLRVKSSDQ

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Macromolecule #3: Translation initiation factor eIF-2B subunit alpha

MacromoleculeName: Translation initiation factor eIF-2B subunit alpha / type: protein_or_peptide / ID: 3 / Details: F6P / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 40.552938 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MDDKELIEYF KSQMKEDPDM ASAVAAIRTL LEFLKRDKGE TIQGLRANLT SAIETLCGVD SSVAVSSGGE LFLRFISLAS LEYSDYSKC KKIMIERGEL FLRRISLSRN KIADLCHTFI KDGATILTHA YSRVVLRVLE AAVAAKKRFS VYVTESQPDL S GKKMAKAL ...String:
MDDKELIEYF KSQMKEDPDM ASAVAAIRTL LEFLKRDKGE TIQGLRANLT SAIETLCGVD SSVAVSSGGE LFLRFISLAS LEYSDYSKC KKIMIERGEL FLRRISLSRN KIADLCHTFI KDGATILTHA YSRVVLRVLE AAVAAKKRFS VYVTESQPDL S GKKMAKAL CHLNVPVTVV LDAAVGYIME KADLVIVGAE GVVENGGIIN KIGTNQMAVC AKAQNKPFYV VAESFKFVRL FP LNQQDVP DKFKYKADTL KVAQTGQDLK EEHPWVDYTA PSLITLLFTD LGVLTPSAVS DELIKLYLGG ENLYFQAEDK GGG SGGGGS GGGGSASQGG LNDIFEAQKI EWHEGGGGSG GGGSGGGGSG RDQDYKDDDD K

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Macromolecule #4: Translation initiation factor eIF-2B subunit epsilon

MacromoleculeName: Translation initiation factor eIF-2B subunit epsilon / type: protein_or_peptide / ID: 4 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 80.466609 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MAAPVVAPPG VVVSRANKRS GAGPGGSGGG GARGAEEEPP PPLQAVLVAD SFDRRFFPIS KDQPRVLLPL ANVALIDYTL EFLTATGVQ ETFVFCCWKA AQIKEHLLKS KWCRPTSLNV VRIITSELYR SLGDVLRDVD AKALVRSDFL LVYGDVISNI N ITRALEEH ...String:
MAAPVVAPPG VVVSRANKRS GAGPGGSGGG GARGAEEEPP PPLQAVLVAD SFDRRFFPIS KDQPRVLLPL ANVALIDYTL EFLTATGVQ ETFVFCCWKA AQIKEHLLKS KWCRPTSLNV VRIITSELYR SLGDVLRDVD AKALVRSDFL LVYGDVISNI N ITRALEEH RLRRKLEKNV SVMTMIFKES SPSHPTRCHE DNVVVAVDST TNRVLHFQKT QGLRRFAFPL SLFQGSSDGV EV RYDLLDC HISICSPQVA QLFTDNFDYQ TRDDFVRGLL VNEEILGNQI HMHVTAKEYG ARVSNLHMYS AVCADVIRRW VYP LTPEAN FTDSTTQSCT HSRHNIYRGP EVSLGHGSIL EENVLLGSGT VIGSNCFITN SVIGPGCHIG DNVVLDQTYL WQGV RVAAG AQIHQSLLCD NAEVKERVTL KPRSVLTSQV VVGPNITLPE GSVISLHPPD AEEDEDDGEF SDDSGADQEK DKVKM KGYN PAEVGAAGKG YLWKAAGMNM EEEEELQQNL WGLKINMEEE SESESEQSMD SEEPDSRGGS PQMDDIKVFQ NEVLGT LQR GKEENISCDN LVLEINSLKY AYNISLKEVM QVLSHVVLEF PLQQMDSPLD SSRYCALLLP LLKAWSPVFR NYIKRAA DH LEALAAIEDF FLEHEALGIS MAKVLMAFYQ LEILAEETIL SWFSQRDTTD KGQQLRKNQQ LQRFIQWLKE AEEESSED D

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Macromolecule #5: Translation initiation factor eIF-2B subunit gamma

MacromoleculeName: Translation initiation factor eIF-2B subunit gamma / type: protein_or_peptide / ID: 5 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 50.30423 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MEFQAVVMAV GGGSRMTDLT SSIPKPLLPV GNKPLIWYPL NLLERVGFEE VIVVTTRDVQ KALCAEFKMK MKPDIVCIPD DADMGTADS LRYIYPKLKT DVLVLSCDLI TDVALHEVVD LFRAYDASLA MLMRKGQDSI EPVPGQKGKK KAVEQRDFIG V DSTGKRLL ...String:
MEFQAVVMAV GGGSRMTDLT SSIPKPLLPV GNKPLIWYPL NLLERVGFEE VIVVTTRDVQ KALCAEFKMK MKPDIVCIPD DADMGTADS LRYIYPKLKT DVLVLSCDLI TDVALHEVVD LFRAYDASLA MLMRKGQDSI EPVPGQKGKK KAVEQRDFIG V DSTGKRLL FMANEADLDE ELVIKGSILQ KHPRIRFHTG LVDAHLYCLK KYIVDFLMEN GSITSIRSEL IPYLVRKQFS SA SSQQGQE EKEEDLKKKE LKSLDIYSFI KEANTLNLAP YDACWNACRG DRWEDLSRSQ VRCYVHIMKE GLCSRVSTLG LYM EANRQV PKLLSALCPE EPPVHSSAQI VSKHLVGVDS LIGPETQIGE KSSIKRSVIG SSCLIKDRVT ITNCLLMNSV TVEE GSNIQ GSVICNNAVI EKGADIKDCL IGSGQRIEAK AKRVNEVIVG NDQLMEI

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Macromolecule #6: 6-O-phosphono-beta-D-fructofuranose

MacromoleculeName: 6-O-phosphono-beta-D-fructofuranose / type: ligand / ID: 6 / Number of copies: 2 / Formula: F6P
Molecular weightTheoretical: 260.136 Da
Chemical component information

ChemComp-F6P:
6-O-phosphono-beta-D-fructofuranose

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Macromolecule #7: water

MacromoleculeName: water / type: ligand / ID: 7 / Number of copies: 18 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.32 mg/mL
BufferpH: 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
VitrificationCryogen name: ETHANE
Detailseif2a was mixed with eif2bcde in 1.5 :1 molar ratio and incubated on ice.

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Number real images: 6073 / Average electron dose: 44.33 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: OTHER
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 2.91 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 2.15) / Number images used: 73704
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 2.15)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 2.15)

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Atomic model buiding 1

Initial modelPDB ID:

6caj

DetailsReal space refinement
RefinementProtocol: RIGID BODY FIT
Output model

PDB-7kmf:
Sugar phosphate activation of the stress sensor eIF2B

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