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- PDB-5eir: Co-crystal structure of eIF4E with nucleotide mimetic inhibitor. -

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Basic information

Entry
Database: PDB / ID: 5eir
TitleCo-crystal structure of eIF4E with nucleotide mimetic inhibitor.
Components
  • Eukaryotic translation initiation factor 4 gamma 1
  • Eukaryotic translation initiation factor 4E
KeywordsTRANSLATION / Complex / inhibitor / eIF4E
Function / homology
Function and homology information


positive regulation of eukaryotic translation initiation factor 4F complex assembly / : / positive regulation of translation in response to endoplasmic reticulum stress / eukaryotic initiation factor 4G binding / cap-dependent translational initiation / Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43S / eukaryotic initiation factor 4E binding / regulation of translation at postsynapse, modulating synaptic transmission / regulation of cellular response to stress / RNA cap binding ...positive regulation of eukaryotic translation initiation factor 4F complex assembly / : / positive regulation of translation in response to endoplasmic reticulum stress / eukaryotic initiation factor 4G binding / cap-dependent translational initiation / Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43S / eukaryotic initiation factor 4E binding / regulation of translation at postsynapse, modulating synaptic transmission / regulation of cellular response to stress / RNA cap binding / eukaryotic translation initiation factor 4F complex / chromatoid body / Z-decay: degradation of maternal mRNAs by zygotically expressed factors / translation factor activity, RNA binding / mRNA cap binding / Deadenylation of mRNA / miRNA-mediated gene silencing by inhibition of translation / RNA 7-methylguanosine cap binding / Transport of the SLBP independent Mature mRNA / Transport of the SLBP Dependant Mature mRNA / M-decay: degradation of maternal mRNAs by maternally stored factors / Transport of Mature mRNA Derived from an Intronless Transcript / RISC complex / regulation of translational initiation / positive regulation of protein localization to cell periphery / Ribosomal scanning and start codon recognition / stem cell population maintenance / negative regulation of neuron differentiation / Translation initiation complex formation / positive regulation of protein metabolic process / mTORC1-mediated signalling / Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC) / GTP hydrolysis and joining of the 60S ribosomal subunit / cellular response to dexamethasone stimulus / L13a-mediated translational silencing of Ceruloplasmin expression / positive regulation of G1/S transition of mitotic cell cycle / regulation of presynapse assembly / behavioral fear response / mRNA export from nucleus / cellular response to nutrient levels / Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC) / energy homeostasis / translation initiation factor binding / translation initiation factor activity / positive regulation of neuron differentiation / positive regulation of mitotic cell cycle / negative regulation of autophagy / AUF1 (hnRNP D0) binds and destabilizes mRNA / translational initiation / P-body / G1/S transition of mitotic cell cycle / ISG15 antiviral mechanism / Regulation of expression of SLITs and ROBOs / cytoplasmic ribonucleoprotein granule / neuron differentiation / cytoplasmic stress granule / regulation of translation / positive regulation of cell growth / molecular adaptor activity / DNA-binding transcription factor binding / postsynapse / negative regulation of translation / nuclear speck / ribosome / translation / mRNA binding / perinuclear region of cytoplasm / glutamatergic synapse / enzyme binding / RNA binding / extracellular exosome / ATP binding / nucleus / membrane / cytoplasm / cytosol
Similarity search - Function
RNA Cap, Translation Initiation Factor Eif4e / RNA Cap, Translation Initiation Factor Eif4e / Eukaryotic translation initiation factor 4E (eIF-4E), conserved site / Eukaryotic initiation factor 4E signature. / Translation Initiation factor eIF- 4e / Eukaryotic initiation factor 4E / Translation Initiation factor eIF- 4e-like / eIF4-gamma/eIF5/eIF2-epsilon / Domain at the C-termini of GCD6, eIF-2B epsilon, eIF-4 gamma and eIF-5 / W2 domain ...RNA Cap, Translation Initiation Factor Eif4e / RNA Cap, Translation Initiation Factor Eif4e / Eukaryotic translation initiation factor 4E (eIF-4E), conserved site / Eukaryotic initiation factor 4E signature. / Translation Initiation factor eIF- 4e / Eukaryotic initiation factor 4E / Translation Initiation factor eIF- 4e-like / 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. / Initiation factor eIF-4 gamma, MA3 / MA3 domain / MI domain profile. / Domain in DAP-5, eIF4G, MA-3 and other proteins. / MIF4G domain / Middle domain of eukaryotic initiation factor 4G (eIF4G) / MIF4G-like, type 3 / Armadillo-type fold / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-5O8 / Eukaryotic translation initiation factor 4E / Eukaryotic translation initiation factor 4 gamma 1
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.69 Å
AuthorsNowicki, M.W. / Walkinshaw, M.D. / Fischer, P.M.
CitationJournal: Eur.J.Med.Chem. / Year: 2016
Title: Design of nucleotide-mimetic and non-nucleotide inhibitors of the translation initiation factor eIF4E: Synthesis, structural and functional characterisation.
Authors: Soukarieh, F. / Nowicki, M.W. / Bastide, A. / Poyry, T. / Jones, C. / Dudek, K. / Patwardhan, G. / Meullenet, F. / Oldham, N.J. / Walkinshaw, M.D. / Willis, A.E. / Fischer, P.M.
History
DepositionOct 30, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Sep 7, 2016Provider: repository / Type: Initial release
Revision 1.1Sep 14, 2016Group: Database references
Revision 1.2Jan 10, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Eukaryotic translation initiation factor 4E
B: Eukaryotic translation initiation factor 4 gamma 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,5834
Polymers26,9812
Non-polymers6022
Water57632
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1550 Å2
ΔGint-26 kcal/mol
Surface area10950 Å2
MethodPISA
Unit cell
Length a, b, c (Å)38.250, 52.120, 123.670
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21221
Components on special symmetry positions
IDModelComponents
11A-404-

HOH

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Components

#1: Protein Eukaryotic translation initiation factor 4E / eIF4E / eIF-4F 25 kDa subunit / mRNA cap-binding protein


Mass: 25130.242 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EIF4E, EIF4EL1, EIF4F / Plasmid: pET11d / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): Rosetta pLysS / References: UniProt: P06730
#2: Protein/peptide Eukaryotic translation initiation factor 4 gamma 1


Mass: 1851.155 Da / Num. of mol.: 1 / Fragment: eIF4E binding sequence / Source method: obtained synthetically / Details: commercial synthesis / Source: (synth.) synthetic construct (others) / References: UniProt: Q04637*PLUS
#3: Chemical ChemComp-5O8 / ~{N}-[[(2~{R},3~{S},4~{R},5~{R})-5-[2-azanyl-6-oxidanylidene-7-(phenylmethyl)-1~{H}-purin-7-ium-9-yl]-3,4-bis(oxidanyl)oxolan-2-yl]methyl]-1,1,1-tris(fluoranyl)methanesulfonamide


Mass: 505.448 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H20F3N6O6S
#4: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 32 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.28 Å3/Da / Density % sol: 46.16 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 21-31% PEG 8000, 1???3% (NH4)2SO4, 100 mM HEPES, pH 7.5, 1 round of seeding. Crystals replaced in to above conditions without (NH4)2SO4 prior to freezing.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.9173 Å
DetectorType: DECTRIS PILATUS 300K / Detector: PIXEL / Date: May 15, 2011 / Details: PILATUS 6M
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9173 Å / Relative weight: 1
ReflectionResolution: 2.69→123.67 Å / Num. all: 6814 / Num. obs: 6814 / % possible obs: 93.8 % / Redundancy: 2.9 % / Biso Wilson estimate: 22.08 Å2 / Rpim(I) all: 0.106 / Rrim(I) all: 0.193 / Rsym value: 0.16 / Net I/av σ(I): 3.5 / Net I/σ(I): 5.5 / Num. measured all: 19790
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRpim(I) allRsym valueNet I/σ(I) obs% possible all
2.69-2.842.80.3592.124318540.2350.359385.8
2.84-3.013.20.2872.630529670.180.2873.897.1
3.01-3.2230.2243.327229030.1430.2244.596.5
3.22-3.4730.1863.625638470.1210.1865.697.2
3.47-3.82.80.1892.821747850.1310.1896.397.6
3.8-4.252.70.1213.716646210.0860.1216.686.7
4.25-4.9130.0957.718476260.060.0957.296.8
4.91-6.022.90.1047.215485390.0680.104795.1
6.02-8.512.60.0927.910504000.0630.0926.689.8
8.51-48.0292.70.04215.87392720.0290.0429.197.2

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Processing

Software
NameVersionClassification
SCALA3.3.16data scaling
PHENIXrefinement
PDB_EXTRACT3.15data extraction
iMOSFLMdata reduction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2V8Y chain A

2v8y


Resolution: 2.69→48.029 Å / SU ML: 0.21 / Cross valid method: NONE / σ(F): 0.29 / Phase error: 25.73 / Stereochemistry target values: MLHL
RfactorNum. reflection% reflection
Rfree0.2723 310 4.6 %
Rwork0.2476 6428 -
obs0.2489 6738 91.85 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 97.52 Å2 / Biso mean: 25.137 Å2 / Biso min: 3.64 Å2
Refinement stepCycle: final / Resolution: 2.69→48.029 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1663 0 73 32 1768
Biso mean--38.28 25.69 -
Num. residues----199
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0091809
X-RAY DIFFRACTIONf_angle_d1.2452463
X-RAY DIFFRACTIONf_chiral_restr0.06253
X-RAY DIFFRACTIONf_plane_restr0.007304
X-RAY DIFFRACTIONf_dihedral_angle_d19.619658
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 2 / % reflection obs: 92 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all
2.6901-3.38910.33271340.276931593293
3.3891-48.03650.24431760.2332693445

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