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- EMDB-7442: Electron cryo-microscopy of the eukaryotic translation initiation... -

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Basic information

Entry
Database: EMDB / ID: EMD-7442
TitleElectron cryo-microscopy of the eukaryotic translation initiation factor 2B from Homo sapiens
Map dataprimary
Sample
  • Complex: Translation initiation factor eIF-2B decamer
    • Protein or peptide: Translation initiation factor eIF-2B subunit epsilon
    • Protein or peptide: Translation initiation factor eIF-2B subunit gamma
    • Protein or peptide: Translation initiation factor eIF-2B subunit alpha
    • Protein or peptide: Translation initiation factor eIF-2B subunit beta
    • Protein or peptide: Translation initiation factor eIF-2B subunit delta
  • Ligand: 2-(4-chloranylphenoxy)-~{N}-[4-[2-(4-chloranylphenoxy)ethanoylamino]cyclohexyl]ethanamide
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 / translation initiation factor binding / ovarian follicle development / translational initiation / myelination / translation initiation factor activity / response to endoplasmic reticulum stress / guanyl-nucleotide exchange factor activity / central nervous system development / hippocampus development / response to peptide hormone / regulation of translation / response to heat / T cell receptor signaling pathway / positive regulation of apoptotic process / GTP binding / ATP binding / membrane / identical protein binding / 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 / 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: 2.8 Å
AuthorsTsai JC / Miller-Vedam LE / Anand AA / Jaishankar P / Nguyen HC / Renslo AR / Frost A / Walter P
Funding support United States, 2 items
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, 2018-
Header (metadata) releaseMar 14, 2018-
Map releaseApr 11, 2018-
UpdateNov 25, 2020-
Current statusNov 25, 2020Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 12
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 12
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6caj
  • Surface level: 12
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-6caj
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_7442.png

Downloads & links

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Map

FileDownload / File: emd_7442.map.gz / Format: CCP4 / Size: 366.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationprimary
Voxel sizeX=Y=Z: 0.838 Å
Density
Contour LevelBy AUTHOR: 4.62 / Movie #1: 12
Minimum - Maximum-54.845497 - 80.43178
Average (Standard dev.)0.054956913 (±1.4694334)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions458458458
Spacing458458458
CellA=B=C: 383.804 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.8380.8380.838
M x/y/z458458458
origin x/y/z0.0000.0000.000
length x/y/z383.804383.804383.804
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS458458458
D min/max/mean-54.84580.4320.055

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Supplemental data

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Sample components

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Entire : Translation initiation factor eIF-2B decamer

EntireName: Translation initiation factor eIF-2B decamer
Components
  • Complex: Translation initiation factor eIF-2B decamer
    • Protein or peptide: Translation initiation factor eIF-2B subunit epsilon
    • Protein or peptide: Translation initiation factor eIF-2B subunit gamma
    • Protein or peptide: Translation initiation factor eIF-2B subunit alpha
    • Protein or peptide: Translation initiation factor eIF-2B subunit beta
    • Protein or peptide: Translation initiation factor eIF-2B subunit delta
  • Ligand: 2-(4-chloranylphenoxy)-~{N}-[4-[2-(4-chloranylphenoxy)ethanoylamino]cyclohexyl]ethanamide

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Supramolecule #1: Translation initiation factor eIF-2B decamer

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

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

MacromoleculeName: Translation initiation factor eIF-2B subunit epsilon / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 80.452586 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 AYNVSLKEVM QVLSHVVLEF PLQQMDSPLD SSRYCALLLP LLKAWSPVFR NYIKRAA DH LEALAAIEDF FLEHEALGIS MAKVLMAFYQ LEILAEETIL SWFSQRDTTD KGQQLRKNQQ LQRFIQWLKE AEEESSED D

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

MacromoleculeName: Translation initiation factor eIF-2B subunit gamma / type: protein_or_peptide / ID: 2 / 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 #3: Translation initiation factor eIF-2B subunit alpha

MacromoleculeName: Translation initiation factor eIF-2B subunit alpha / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 33.754148 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 DELIKLYL

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

MacromoleculeName: Translation initiation factor eIF-2B subunit beta / type: protein_or_peptide / ID: 4 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 41.008578 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MHHHHHHGGG SENLYFQSPG SAAKGSELSE RIESFVETLK RGGGPRSSEE MARETLGLLR QIITDHRWSN AGELMELIRR EGRRMTAAQ PSETTVGNMV RRVLKIIREE YGRLHGRSDE SDQQESLHKL LTSGGLNEDF SFHYAQLQSN IIEAINELLV E LEGTMENI ...String:
MHHHHHHGGG SENLYFQSPG SAAKGSELSE RIESFVETLK RGGGPRSSEE MARETLGLLR QIITDHRWSN AGELMELIRR EGRRMTAAQ PSETTVGNMV RRVLKIIREE YGRLHGRSDE SDQQESLHKL LTSGGLNEDF SFHYAQLQSN IIEAINELLV E LEGTMENI AAQALEHIHS NEVIMTIGFS RTVEAFLKEA ARKRKFHVIV AECAPFCQGH EMAVNLSKAG IETTVMTDAA IF AVMSRVN KVIIGTKTIL ANGALRAVTG THTLALAAKH HSTPLIVCAP MFKLSPQFPN EEDSFHKFVA PEEVLPFTEG DIL EKVSVH CPVFDYVPPE LITLFISNIG GNAPSYIYRL MSELYHPDDH VL

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

MacromoleculeName: Translation initiation factor eIF-2B subunit delta / type: protein_or_peptide / ID: 5 / 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 #6: 2-(4-chloranylphenoxy)-~{N}-[4-[2-(4-chloranylphenoxy)ethanoylami...

MacromoleculeName: 2-(4-chloranylphenoxy)-~{N}-[4-[2-(4-chloranylphenoxy)ethanoylamino]cyclohexyl]ethanamide
type: ligand / ID: 6 / Number of copies: 1 / Formula: C7B
Molecular weightTheoretical: 451.343 Da
Chemical component information

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

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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

BufferpH: 7.5
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Average electron dose: 1.63 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 202125
CTF correctionSoftware - Name: Gctf (ver. 1.06)
Startup modelType of model: NONE
Details: initial model generated using cryoSPARC ab-initio modeling
Initial angle assignmentType: ANGULAR RECONSTITUTION / Software - Name: RELION (ver. 2.0)
Final angle assignmentType: ANGULAR RECONSTITUTION / Software - Name: FREALIGN
Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 2.8 Å / Resolution method: FSC 0.5 CUT-OFF / Software - Name: FREALIGN / Number images used: 202125

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-6caj:
Electron cryo-microscopy of the eukaryotic translation initiation factor 2B from Homo sapiens

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