6CAJ

Electron cryo-microscopy of the eukaryotic translation initiation factor 2B from Homo sapiens


Experimental Data Snapshot

  • Method: ELECTRON MICROSCOPY
  • Resolution: 2.80 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

Structure of the nucleotide exchange factor eIF2B reveals mechanism of memory-enhancing molecule.

Tsai, J.C.Miller-Vedam, L.E.Anand, A.A.Jaishankar, P.Nguyen, H.C.Renslo, A.R.Frost, A.Walter, P.

(2018) Science 359

  • DOI: https://doi.org/10.1126/science.aaq0939
  • Primary Citation of Related Structures:  
    6CAJ

  • PubMed 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 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.


  • Organizational Affiliation

    Howard Hughes Medical Institute, University of California, San Francisco, CA, USA.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Translation initiation factor eIF-2B subunit epsilonA [auth B],
F [auth A]
721Homo sapiensMutation(s): 1 
Gene Names: EIF2B5EIF2BE
UniProt & NIH Common Fund Data Resources
Find proteins for Q13144 (Homo sapiens)
Explore Q13144 
Go to UniProtKB:  Q13144
PHAROS:  Q13144
GTEx:  ENSG00000145191 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ13144
Sequence Annotations
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Translation initiation factor eIF-2B subunit gammaB [auth J],
G [auth I]
452Homo sapiensMutation(s): 0 
Gene Names: EIF2B3
UniProt & NIH Common Fund Data Resources
Find proteins for Q9NR50 (Homo sapiens)
Explore Q9NR50 
Go to UniProtKB:  Q9NR50
PHAROS:  Q9NR50
GTEx:  ENSG00000070785 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9NR50
Sequence Annotations
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  • Reference Sequence
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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Translation initiation factor eIF-2B subunit alphaC [auth H],
H [auth G]
305Homo sapiensMutation(s): 0 
Gene Names: EIF2B1EIF2BA
UniProt & NIH Common Fund Data Resources
Find proteins for Q14232 (Homo sapiens)
Explore Q14232 
Go to UniProtKB:  Q14232
PHAROS:  Q14232
GTEx:  ENSG00000111361 
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UniProt GroupQ14232
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  • Reference Sequence
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Entity ID: 4
MoleculeChains Sequence LengthOrganismDetailsImage
Translation initiation factor eIF-2B subunit betaD [auth C],
I [auth D]
368Homo sapiensMutation(s): 0 
Gene Names: EIF2B2EIF2BB
UniProt & NIH Common Fund Data Resources
Find proteins for P49770 (Homo sapiens)
Explore P49770 
Go to UniProtKB:  P49770
PHAROS:  P49770
GTEx:  ENSG00000119718 
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UniProt GroupP49770
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  • Reference Sequence
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Entity ID: 5
MoleculeChains Sequence LengthOrganismDetailsImage
Translation initiation factor eIF-2B subunit deltaE [auth F],
J [auth E]
523Homo sapiensMutation(s): 0 
Gene Names: EIF2B4EIF2BD
UniProt & NIH Common Fund Data Resources
Find proteins for Q9UI10 (Homo sapiens)
Explore Q9UI10 
Go to UniProtKB:  Q9UI10
PHAROS:  Q9UI10
GTEx:  ENSG00000115211 
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UniProt GroupQ9UI10
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
C7B
Query on C7B

Download Ideal Coordinates CCD File 
K [auth C]2-(4-chloranylphenoxy)-~{N}-[4-[2-(4-chloranylphenoxy)ethanoylamino]cyclohexyl]ethanamide
C22 H24 Cl2 N2 O4
HJGMCDHQPXTGAV-IYARVYRRSA-N
Experimental Data & Validation

Experimental Data

  • Method: ELECTRON MICROSCOPY
  • Resolution: 2.80 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 
EM Software:
TaskSoftware PackageVersion
RECONSTRUCTIONFREALIGN
MODEL REFINEMENTPHENIX

Structure Validation

View Full Validation Report



Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Howard Hughes Medical Institute (HHMI)United StatesFaculty Scholar 55108523
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United States1DP2GM110772-01

Revision History  (Full details and data files)

  • Version 1.0: 2018-04-11
    Type: Initial release
  • Version 1.1: 2019-02-20
    Changes: Author supporting evidence, Data collection
  • Version 1.2: 2019-11-20
    Changes: Author supporting evidence, Database references, Structure summary