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

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Basic information

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


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 translation at postsynapse, modulating synaptic transmission / Z-decay: degradation of maternal mRNAs by zygotically expressed factors / RNA cap binding / chromatoid body / eukaryotic translation initiation factor 4F complex / Deadenylation of mRNA / mRNA cap binding ...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 translation at postsynapse, modulating synaptic transmission / Z-decay: degradation of maternal mRNAs by zygotically expressed factors / RNA cap binding / chromatoid body / eukaryotic translation initiation factor 4F complex / Deadenylation of mRNA / mRNA cap binding / Transport of the SLBP independent Mature mRNA / M-decay: degradation of maternal mRNAs by maternally stored factors / Transport of the SLBP Dependant Mature mRNA / RNA 7-methylguanosine cap binding / Transport of Mature mRNA Derived from an Intronless Transcript / RISC complex / Translation initiation complex formation / Ribosomal scanning and start codon recognition / stem cell population maintenance / mTORC1-mediated signalling / L13a-mediated translational silencing of Ceruloplasmin expression / GTP hydrolysis and joining of the 60S ribosomal subunit / negative regulation of neuron differentiation / TOR signaling / behavioral fear response / mRNA export from nucleus / translation repressor activity / negative regulation of translational initiation / translation initiation factor binding / translational initiation / translation initiation factor activity / positive regulation of mitotic cell cycle / cellular response to dexamethasone stimulus / P-body / neuron differentiation / ISG15 antiviral mechanism / cytoplasmic ribonucleoprotein granule / cytoplasmic stress granule / G1/S transition of mitotic cell cycle / regulation of translation / postsynapse / DNA-binding transcription factor binding / negative regulation of translation / nuclear speck / glutamatergic synapse / perinuclear region of cytoplasm / enzyme binding / RNA binding / extracellular exosome / nucleus / cytoplasm / cytosol
Similarity search - Function
Eukaryotic translation initiation factor 4E binding / Eukaryotic translation initiation factor 4E binding protein (EIF4EBP) / 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 / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-5PQ / Eukaryotic translation initiation factor 4E / Eukaryotic translation initiation factor 4E-binding protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.61 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
DepositionNov 4, 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

Downloads & links

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Assembly

Deposited unit
A: Eukaryotic translation initiation factor 4E
B: Eukaryotic translation initiation factor 4E-binding protein 1
C: Eukaryotic translation initiation factor 4E
D: Eukaryotic translation initiation factor 4E-binding protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)54,7706
Polymers53,9834
Non-polymers7872
Water00
1
A: Eukaryotic translation initiation factor 4E
B: Eukaryotic translation initiation factor 4E-binding protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,3853
Polymers26,9912
Non-polymers3931
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1330 Å2
ΔGint-7 kcal/mol
Surface area10570 Å2
MethodPISA
2
C: Eukaryotic translation initiation factor 4E
D: Eukaryotic translation initiation factor 4E-binding protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,3853
Polymers26,9912
Non-polymers3931
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1400 Å2
ΔGint-7 kcal/mol
Surface area9920 Å2
MethodPISA
Unit cell
Length a, b, c (Å)38.480, 100.780, 136.460
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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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.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EIF4E, EIF4EL1, EIF4F / Plasmid: pET11d / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / Variant (production host): Rosetta PLysS / References: UniProt: P06730
#2: Protein/peptide Eukaryotic translation initiation factor 4E-binding protein 1 / eIF4E-binding protein 1 / Phosphorylated heat- and acid-stable protein regulated by insulin 1 / PHAS-I


Mass: 1861.240 Da / Num. of mol.: 2 / Fragment: eIF4E binding sequence, UNP residues 51-64 / Source method: obtained synthetically / Details: Natural sequence from 4EBP / Source: (synth.) Homo sapiens (human) / References: UniProt: Q13541
#3: Chemical ChemComp-5PQ / 3-[[(2~{R},3~{S},4~{R},5~{R})-5-(2-azanyl-7-methyl-6-oxidanylidene-1~{H}-purin-7-ium-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methylamino]-4-oxidanyl-cyclobut-3-ene-1,2-dione


Mass: 393.331 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C15H17N6O7

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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: 2.45 Å3/Da / Density % sol: 49.81 %
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: I04 / Wavelength: 0.9763 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jul 3, 2010 / Details: PILATUS 6M
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 3.61→81.068 Å / Num. all: 6413 / Num. obs: 6413 / % possible obs: 97.8 % / Redundancy: 3.3 % / Rpim(I) all: 0.179 / Rrim(I) all: 0.336 / Rsym value: 0.282 / Net I/av σ(I): 2.522 / Net I/σ(I): 4.6 / Num. measured all: 21083
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
3.61-3.813.40.4231.729878890.2640.4233.195.5
3.81-4.043.40.3522.128528470.2210.3523.696.3
4.04-4.313.30.2922.527058110.1850.2924.297.7
4.31-4.663.30.2443.125397630.1540.244599
4.66-5.113.30.2562.923637060.1620.2564.798.1
5.11-5.713.30.3042.421796590.1920.3044.299.4
5.71-6.593.30.358219095810.2280.3583.698.1
6.59-8.073.10.2662.715364980.1770.2664.198.9
8.07-11.423.20.0987.613304120.0640.0989.499.7
11.42-50.392.80.0827.16832470.0590.0821096.6

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Processing

Software
NameVersionClassification
SCALA3.3.9data scaling
PHENIXrefinement
PDB_EXTRACT3.15data extraction
iMOSFLMdata reduction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2V8W

2v8w


Resolution: 3.61→50.39 Å / SU ML: 0.52 / Cross valid method: NONE / σ(F): 1.34 / Phase error: 31.63 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.3417 301 4.72 %
Rwork0.2665 6082 -
obs0.2701 6383 97.24 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 31.05 Å2 / Biso mean: 18.8734 Å2 / Biso min: 14.71 Å2
Refinement stepCycle: final / Resolution: 3.61→50.39 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3209 0 56 0 3265
Biso mean--21.03 --
Num. residues----384
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0033348
X-RAY DIFFRACTIONf_angle_d0.7644530
X-RAY DIFFRACTIONf_chiral_restr0.047471
X-RAY DIFFRACTIONf_plane_restr0.004567
X-RAY DIFFRACTIONf_dihedral_angle_d17.6531243
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 2

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
3.6102-4.5480.34811440.28122931307596
4.548-50.39490.33531570.25193151330898

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