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- PDB-5ei3: Co-crystal structure of eIF4E with nucleotide mimetic inhibitor. -

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Basic information

Entry
Database: PDB / ID: 5ei3
TitleCo-crystal structure of eIF4E with nucleotide mimetic inhibitor.
Components
  • Eukaryotic translation initiation factor 4 gammaEukaryotic translation initiation factor 4 gamma 1
  • Eukaryotic translation initiation factor 4EEIF4E
KeywordsTRANSLATION / Complex / inhibitor / eIF4E
Function / homology
Function and homology information


positive regulation of eukaryotic translation initiation factor 4F complex assembly / positive regulation of mRNA cap binding / positive regulation of translation in response to endoplasmic reticulum stress / cap-dependent translational initiation / macromolecule biosynthetic process / Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43S / eukaryotic initiation factor 4G binding / eukaryotic initiation factor 4E binding / regulation of cellular response to stress / regulation of translation at postsynapse, modulating synaptic transmission ...positive regulation of eukaryotic translation initiation factor 4F complex assembly / positive regulation of mRNA cap binding / positive regulation of translation in response to endoplasmic reticulum stress / cap-dependent translational initiation / macromolecule biosynthetic process / Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43S / eukaryotic initiation factor 4G binding / eukaryotic initiation factor 4E binding / regulation of cellular response to stress / regulation of translation at postsynapse, modulating synaptic transmission / RNA cap binding / chromatoid body / eukaryotic translation initiation factor 4F complex / 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 / positive regulation of protein localization to cell periphery / RISC complex / regulation of translational initiation / Ribosomal scanning and start codon recognition / Translation initiation complex formation / stem cell population maintenance / negative regulation of peptidyl-threonine phosphorylation / mTORC1-mediated signalling / cellular response to nutrient levels / regulation of presynapse assembly / Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC) / GTP hydrolysis and joining of the 60S ribosomal subunit / negative regulation of neuron differentiation / L13a-mediated translational silencing of Ceruloplasmin expression / positive regulation of G1/S transition of mitotic cell cycle / behavioral fear response / Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC) / mRNA export from nucleus / translation initiation factor binding / energy homeostasis / translational initiation / translation initiation factor activity / positive regulation of protein metabolic process / positive regulation of neuron differentiation / cellular response to dexamethasone stimulus / positive regulation of mitotic cell cycle / negative regulation of autophagy / AUF1 (hnRNP D0) binds and destabilizes mRNA / P-body / lung development / G1/S transition of mitotic cell cycle / cytoplasmic ribonucleoprotein granule / neuron differentiation / ISG15 antiviral mechanism / Regulation of expression of SLITs and ROBOs / cytoplasmic stress granule / regulation of translation / positive regulation of peptidyl-serine phosphorylation / postsynapse / positive regulation of cell growth / response to ethanol / DNA-binding transcription factor binding / negative regulation of translation / molecular adaptor activity / ribosome / nuclear speck / translation / mRNA binding / glutamatergic synapse / perinuclear region of cytoplasm / enzyme binding / RNA binding / extracellular exosome / ATP binding / membrane / identical protein binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Initiation factor 4G / 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 / eIF4-gamma/eIF5/eIF2-epsilon / Domain at the C-termini of GCD6, eIF-2B epsilon, eIF-4 gamma and eIF-5 / Translation Initiation factor eIF- 4e-like ...Initiation factor 4G / 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 / eIF4-gamma/eIF5/eIF2-epsilon / Domain at the C-termini of GCD6, eIF-2B epsilon, eIF-4 gamma and eIF-5 / Translation Initiation factor eIF- 4e-like / 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: 1.71 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 29, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Sep 7, 2016Provider: repository / Type: Initial release
Revision 1.1Sep 14, 2016Group: Database references
Revision 1.2Nov 29, 2017Group: Database references / Category: pdbx_database_related
Revision 2.0Jan 10, 2024Group: Atomic model / Data collection ...Atomic model / Data collection / Database references / Refinement description
Category: atom_site / chem_comp_atom ...atom_site / chem_comp_atom / chem_comp_bond / database_2 / diffrn_radiation_wavelength / pdbx_initial_refinement_model
Item: _atom_site.occupancy / _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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,5834
Polymers26,9812
Non-polymers6022
Water6,395355
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1590 Å2
ΔGint-23 kcal/mol
Surface area11170 Å2
MethodPISA
Unit cell
Length a, b, c (Å)38.590, 52.080, 125.190
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-511-

HOH

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Components

#1: Protein Eukaryotic translation initiation factor 4E / EIF4E / 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 / 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 / Sulfate


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


Mass: 18.015 Da / Num. of mol.: 355 / 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: 2.33 Å3/Da / Density % sol: 47.24 %
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

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I02 / Wavelength: 0.85 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Apr 30, 2011 / Details: PSI PILATUS 6M
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.85 Å / Relative weight: 1
ReflectionResolution: 1.71→62.595 Å / Num. all: 28165 / Num. obs: 28165 / % possible obs: 100 % / Redundancy: 7 % / Biso Wilson estimate: 11.24 Å2 / Rpim(I) all: 0.039 / Rrim(I) all: 0.102 / Rsym value: 0.094 / Net I/av σ(I): 4.843 / Net I/σ(I): 15.7 / Num. measured all: 195799
Reflection shell

Diffraction-ID: 1 / Rejects: 0

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRpim(I) allRsym valueNet I/σ(I) obs% possible all
1.71-1.87.10.3422.22875940390.1380.3425.3100
1.8-1.917.10.2373.22719838210.0950.2377.4100
1.91-2.047.10.1654.52559136050.0670.16510.2100
2.04-2.217.10.1231.92370733520.050.12313.5100
2.21-2.4270.16.42200631300.0410.115.6100
2.42-2.770.0788.71973528260.0310.07818.2100
2.7-3.126.90.0718.81728425210.0290.07122.4100
3.12-3.826.60.0668.91422721570.0280.06627.1100
3.82-5.416.40.0678.31090517050.0290.06734.5100
5.41-40.0356.30.03915638710090.0170.03936.299.5

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Processing

Software
NameVersionClassification
SCALA3.3.16data scaling
PHENIXrefinement
PDB_EXTRACT3.15data extraction
MOSFLMdata reduction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2v8w

2v8w


Resolution: 1.71→40.035 Å / SU ML: 0.16 / Cross valid method: NONE / σ(F): 1.7 / Phase error: 16.73 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1873 1411 5.02 %
Rwork0.1656 26678 -
obs0.1667 28089 99.86 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 72.63 Å2 / Biso mean: 16.2 Å2 / Biso min: 3.48 Å2
Refinement stepCycle: final / Resolution: 1.71→40.035 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1703 0 39 355 2097
Biso mean--23.06 25.68 -
Num. residues----205
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0071794
X-RAY DIFFRACTIONf_angle_d0.9462432
X-RAY DIFFRACTIONf_chiral_restr0.063252
X-RAY DIFFRACTIONf_plane_restr0.005305
X-RAY DIFFRACTIONf_dihedral_angle_d16.473658
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 10 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all
1.71-1.77110.24181180.198826392757
1.7711-1.8420.22931160.180126452761
1.842-1.92590.19651470.174226262773
1.9259-2.02740.19281260.173526412767
2.0274-2.15440.19451360.168426332769
2.1544-2.32080.22381360.161126382774
2.3208-2.55430.14771510.170926592810
2.5543-2.92380.16811500.167126722822
2.9238-3.68320.19741540.157726922846
3.6832-40.04590.17221770.152928333010

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