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- PDB-8qm4: Potential drug binding sites for translation initiation factor eIF4E -

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Basic information

Entry
Database: PDB / ID: 8qm4
TitlePotential drug binding sites for translation initiation factor eIF4E
ComponentsEukaryotic translation initiation factor 4E
KeywordsTRANSLATION / translation initiation factor / translation regulator / protein biosynthesis / RNA binding
Function / homology
Function and homology information


eukaryotic initiation factor 4G binding / Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43S / regulation of translation at postsynapse, modulating synaptic transmission / RNA cap binding / eukaryotic translation initiation factor 4F complex / chromatoid body / Z-decay: degradation of maternal mRNAs by zygotically expressed factors / mRNA cap binding / Deadenylation of mRNA / RNA 7-methylguanosine cap binding ...eukaryotic initiation factor 4G binding / Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43S / regulation of translation at postsynapse, modulating synaptic transmission / RNA cap binding / eukaryotic translation initiation factor 4F complex / chromatoid body / Z-decay: degradation of maternal mRNAs by zygotically expressed factors / mRNA cap binding / Deadenylation of mRNA / 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 / Ribosomal scanning and start codon recognition / stem cell population maintenance / Translation initiation complex formation / mTORC1-mediated signalling / negative regulation of neuron differentiation / GTP hydrolysis and joining of the 60S ribosomal subunit / L13a-mediated translational silencing of Ceruloplasmin expression / behavioral fear response / mRNA export from nucleus / translation initiation factor activity / positive regulation of mitotic cell cycle / cellular response to dexamethasone stimulus / translational initiation / P-body / neuron differentiation / ISG15 antiviral mechanism / cytoplasmic ribonucleoprotein granule / G1/S transition of mitotic cell cycle / cytoplasmic stress granule / regulation of translation / DNA-binding transcription factor binding / postsynapse / negative regulation of translation / nuclear speck / perinuclear region of cytoplasm / glutamatergic synapse / enzyme binding / RNA binding / extracellular exosome / nucleus / cytosol / cytoplasm
Similarity search - Function
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
Similarity search - Domain/homology
TRIETHYLENE GLYCOL / : / Eukaryotic translation initiation factor 4E
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.849 Å
AuthorsCleasby, A.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Commun / Year: 2024
Title: Integrating fragment-based screening with targeted protein degradation and genetic rescue to explore eIF4E function.
Authors: Sharp, S.Y. / Martella, M. / D'Agostino, S. / Milton, C.I. / Ward, G. / Woodhead, A.J. / Richardson, C.J. / Carr, M.G. / Chiarparin, E. / Cons, B.D. / Coyle, J. / East, C.E. / Hiscock, S.D. ...Authors: Sharp, S.Y. / Martella, M. / D'Agostino, S. / Milton, C.I. / Ward, G. / Woodhead, A.J. / Richardson, C.J. / Carr, M.G. / Chiarparin, E. / Cons, B.D. / Coyle, J. / East, C.E. / Hiscock, S.D. / Martinez-Fleites, C. / Mortenson, P.N. / Palmer, N. / Pathuri, P. / Powers, M.V. / Saalau, S.M. / St Denis, J.D. / Swabey, K. / Vinkovic, M. / Walton, H. / Williams, G. / Clarke, P.A.
History
DepositionSep 21, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 15, 2025Provider: repository / Type: Initial release
Revision 1.1Mar 12, 2025Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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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 4E
hetero molecules


Theoretical massNumber of molelcules
Total (without water)50,8268
Polymers50,0292
Non-polymers7976
Water2,162120
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2440 Å2
ΔGint13 kcal/mol
Surface area20160 Å2
MethodPISA
Unit cell
Length a, b, c (Å)47.152, 69.427, 63.818
Angle α, β, γ (deg.)90.00, 95.92, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Eukaryotic translation initiation factor 4E


Mass: 25014.445 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EIF4E / Production host: Escherichia coli (E. coli) / Strain (production host): BL21-Codon plus (DE3) RIPL / References: UniProt: P06730
#2: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#3: Chemical ChemComp-PGE / TRIETHYLENE GLYCOL


Mass: 150.173 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C6H14O4
#4: Chemical ChemComp-W5B / 3-phenylphenol


Mass: 170.207 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C12H10O / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 120 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 2.08 Å3/Da / Density % sol: 40.77 %
Crystal growTemperature: 273 K / Method: vapor diffusion, sitting drop / pH: 7.5 / Details: 0.002M DTT, 40% PEG 400, 0.1M pH=7.5 HEPES/NaOH

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID29 / Wavelength: 0.97625 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Sep 25, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97625 Å / Relative weight: 1
ReflectionResolution: 1.84→69.427 Å / Num. obs: 35127 / % possible obs: 98.9 % / Redundancy: 3.3 % / Rrim(I) all: 0.048 / Net I/σ(I): 14.7
Reflection shellResolution: 1.85→1.86 Å / Num. unique obs: 694 / Rrim(I) all: 0.714 / % possible all: 99.29

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Processing

Software
NameVersionClassification
BUSTER2.11.8 (16-JUL-2021)refinement
XDSdata reduction
SCALAdata scaling
BUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.849→63.48 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.953 / SU R Cruickshank DPI: 0.242 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.143 / SU Rfree Blow DPI: 0.124 / SU Rfree Cruickshank DPI: 0.127
Details: HYDROGENS WERE FULLY REFINED WITH FULL OCCUPANCY AT NUCLEAR POSITION.
RfactorNum. reflection% reflectionSelection details
Rfree0.2169 1734 5 %RANDOM
Rwork0.1933 ---
obs0.1945 34696 98.8 %-
Displacement parametersBiso mean: 47.324 Å2
Baniso -1Baniso -2Baniso -3
1--2.4284 Å20 Å2-0.2374 Å2
2--5.0827 Å20 Å2
3----2.6543 Å2
Refine analyzeLuzzati coordinate error obs: 0.22 Å
Refinement stepCycle: LAST / Resolution: 1.849→63.48 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3299 0 54 120 3473
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0136722HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0712059HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1474SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes1073HARMONIC16
X-RAY DIFFRACTIONt_it6722HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion6.63
X-RAY DIFFRACTIONt_other_torsion16.42
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion420SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact5081SEMIHARMONIC4
LS refinement shellResolution: 1.85→1.86 Å / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.3007 -6.05 %
Rwork0.2552 652 -
all0.2577 694 -
obs--99.29 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.40710.06960.02721.3399-0.24740.44070.0713-0.04810.14550.0262-0.02430.07060.09090.0499-0.047-0.0463-0.01570.0093-0.03430.00510.058420.7907-13.81894.5374
20.863-0.3666-0.69851.71380.48531.5575-0.0594-0.1913-0.087-0.14650.01740.2241-0.06060.19410.0420.088-0.00570.005-0.07780.0242-0.05521.8603-21.298231.9892
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|11 - A|217 }
2X-RAY DIFFRACTION2{ B|9 - B|217 }

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