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Yorodumi- EMDB-41566: Eukaryotic translation initiation factor 2B with a mutation (L516... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-41566 | |||||||||
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Title | Eukaryotic translation initiation factor 2B with a mutation (L516A) in the delta subunit | |||||||||
Map data | ||||||||||
Sample |
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Keywords | Protein translation / eIF2B / integrated stress response / TRANSLATION | |||||||||
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 / myelination / translation initiation factor activity / response to endoplasmic reticulum stress / guanyl-nucleotide exchange factor activity / central nervous system development / translational initiation / 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 / cytosol / cytoplasm Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.9 Å | |||||||||
Authors | Wang L / Lawrence R / Sangwan S / Anand A / Shoemaker S / Deal A / Marqusee S / Watler P | |||||||||
Funding support | United States, 2 items
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Citation | Journal: Nat Chem Biol / Year: 2024 Title: A helical fulcrum in eIF2B coordinates allosteric regulation of stress signaling. Authors: Rosalie E Lawrence / Sophie R Shoemaker / Aniliese Deal / Smriti Sangwan / Aditya A Anand / Lan Wang / Susan Marqusee / Peter Walter / Abstract: The integrated stress response (ISR) enables cells to survive a variety of acute stresses, but chronic activation of the ISR underlies age-related diseases. ISR signaling downregulates translation ...The integrated stress response (ISR) enables cells to survive a variety of acute stresses, but chronic activation of the ISR underlies age-related diseases. ISR signaling downregulates translation and activates expression of stress-responsive factors that promote return to homeostasis and is initiated by inhibition of the decameric guanine nucleotide exchange factor eIF2B. Conformational and assembly transitions regulate eIF2B activity, but the allosteric mechanisms controlling these dynamic transitions and mediating the therapeutic effects of the small-molecule ISR inhibitor ISRIB are unknown. Using hydrogen-deuterium exchange-mass spectrometry and cryo-electron microscopy, we identified a central α-helix whose orientation allosterically coordinates eIF2B conformation and assembly. Biochemical and cellular signaling assays show that this 'switch-helix' controls eIF2B activity and signaling. In sum, the switch-helix acts as a fulcrum of eIF2B conformational regulation and is a highly conserved actuator of ISR signal transduction. This work uncovers a conserved allosteric mechanism and unlocks new therapeutic possibilities for ISR-linked diseases. | |||||||||
History |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_41566.map.gz | 230.4 MB | EMDB map data format | |
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Header (meta data) | emd-41566-v30.xml emd-41566.xml | 20.1 KB 20.1 KB | Display Display | EMDB header |
Images | emd_41566.png | 39 KB | ||
Filedesc metadata | emd-41566.cif.gz | 7 KB | ||
Others | emd_41566_half_map_1.map.gz emd_41566_half_map_2.map.gz | 226.3 MB 226.3 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-41566 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-41566 | HTTPS FTP |
-Validation report
Summary document | emd_41566_validation.pdf.gz | 1 MB | Display | EMDB validaton report |
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Full document | emd_41566_full_validation.pdf.gz | 1 MB | Display | |
Data in XML | emd_41566_validation.xml.gz | 15.7 KB | Display | |
Data in CIF | emd_41566_validation.cif.gz | 18.4 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-41566 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-41566 | HTTPS FTP |
-Related structure data
Related structure data | 8tqzMC 8tqoC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_41566.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||
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Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 0.835 Å | ||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #2
File | emd_41566_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_41566_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : Translation initiation factor 2B decamer
Entire | Name: Translation initiation factor 2B decamer |
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Components |
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-Supramolecule #1: Translation initiation factor 2B decamer
Supramolecule | Name: Translation initiation factor 2B decamer / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 530 KDa |
-Macromolecule #1: Translation initiation factor eIF-2B subunit alpha
Macromolecule | Name: Translation initiation factor eIF-2B subunit alpha / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 35.723184 KDa |
Recombinant expression | Organism: Escherichia coli (E. coli) |
Sequence | String: MHHHHHHGGG SENLYFQSDD KELIEYFKSQ MKEDPDMASA VAAIRTLLEF LKRDKGETIQ GLRANLTSAI ETLCGVDSSV AVSSGGELF LRFISLASLE YSDYSKCKKI MIERGELFLR RISLSRNKIA DLCHTFIKDG ATILTHAYSR VVLRVLEAAV A AKKRFSVY ...String: MHHHHHHGGG SENLYFQSDD KELIEYFKSQ MKEDPDMASA VAAIRTLLEF LKRDKGETIQ GLRANLTSAI ETLCGVDSSV AVSSGGELF LRFISLASLE YSDYSKCKKI MIERGELFLR RISLSRNKIA DLCHTFIKDG ATILTHAYSR VVLRVLEAAV A AKKRFSVY VTESQPDLSG KKMAKALCHL NVPVTVVLDA AVGYIMEKAD LVIVGAEGVV ENGGIINKIG TNQMAVCAKA QN KPFYVVA ESFKFVRLFP LNQQDVPDKF KYKADTLKVA QTGQDLKEEH PWVDYTAPSL ITLLFTDLGV LTPSAVSDEL IKL YL UniProtKB: Translation initiation factor eIF2B subunit alpha |
-Macromolecule #2: Translation initiation factor eIF-2B subunit epsilon
Macromolecule | Name: Translation initiation factor eIF-2B subunit epsilon / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 80.452586 KDa |
Recombinant expression | Organism: Escherichia coli (E. coli) |
Sequence | String: 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 UniProtKB: Translation initiation factor eIF2B subunit epsilon |
-Macromolecule #3: Translation initiation factor eIF-2B subunit beta
Macromolecule | Name: Translation initiation factor eIF-2B subunit beta / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 41.008578 KDa |
Recombinant expression | Organism: Escherichia coli (E. coli) |
Sequence | String: 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 UniProtKB: Translation initiation factor eIF2B subunit beta |
-Macromolecule #4: Translation initiation factor eIF-2B subunit delta
Macromolecule | Name: Translation initiation factor eIF-2B subunit delta / type: protein_or_peptide / ID: 4 / Number of copies: 2 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 57.59809 KDa |
Recombinant expression | Organism: Escherichia coli (E. coli) |
Sequence | String: 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 VARVKSSDQ UniProtKB: Translation initiation factor eIF2B subunit delta |
-Macromolecule #5: Translation initiation factor eIF-2B subunit gamma
Macromolecule | Name: Translation initiation factor eIF-2B subunit gamma / type: protein_or_peptide / ID: 5 / Number of copies: 2 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 50.30423 KDa |
Recombinant expression | Organism: Escherichia coli (E. coli) |
Sequence | String: 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 UniProtKB: Translation initiation factor eIF2B subunit gamma |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.5 |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 45.8 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
-Image processing
Startup model | Type of model: PDB ENTRY PDB model - PDB ID: |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 327000 |
Initial angle assignment | Type: MAXIMUM LIKELIHOOD |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |