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- PDB-8qm9: Potential drug binding sites for translation initiation factor eIF4E -

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Basic information

Entry
Database: PDB / ID: 8qm9
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 / Transport of the SLBP independent Mature mRNA ...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 / Transport of the SLBP independent Mature mRNA / Transport of the SLBP Dependant Mature mRNA / RNA 7-methylguanosine cap binding / M-decay: degradation of maternal mRNAs by maternally stored factors / Transport of Mature mRNA Derived from an Intronless Transcript / RISC complex / stem cell population maintenance / Ribosomal scanning and start codon recognition / Translation initiation complex formation / mTORC1-mediated signalling / negative regulation of neuron differentiation / GTP hydrolysis and joining of the 60S ribosomal subunit / behavioral fear response / L13a-mediated translational silencing of Ceruloplasmin expression / mRNA export from nucleus / translation initiation factor activity / positive regulation of mitotic cell cycle / cellular response to dexamethasone stimulus / translational initiation / P-body / ISG15 antiviral mechanism / G1/S transition of mitotic cell cycle / cytoplasmic ribonucleoprotein granule / neuron differentiation / 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
DI(HYDROXYETHYL)ETHER / : / Eukaryotic translation initiation factor 4E
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 1.973 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)51,49113
Polymers50,0292
Non-polymers1,46211
Water5,152286
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, monomer in solution
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2940 Å2
ΔGint25 kcal/mol
Surface area20700 Å2
MethodPISA
Unit cell
Length a, b, c (Å)47.284, 69.273, 64.656
Angle α, β, γ (deg.)90.00, 95.71, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 2 molecules AB

#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-CodonPlus (DE3)-RIPL / References: UniProt: P06730

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Non-polymers , 5 types, 297 molecules

#2: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#3: Chemical
ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C4H10O3
#4: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Chemical ChemComp-W4K / (2~{R})-2-[(1~{S})-1-[4-(2-fluorophenyl)-2-(2-hydroxyethylamino)phenyl]propoxy]propan-1-ol


Mass: 347.424 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H26FNO3 / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 286 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.11 Å3/Da / Density % sol: 41.6 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8 / Details: 0.002M DTT 38% PEG 400 0.1M pH=8 Tris/HCl

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-X / Wavelength: 1.54178 Å
DetectorType: DECTRIS PILATUS 300K / Detector: PIXEL / Date: Jun 10, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 1.973→64.33 Å / Num. obs: 27418 / % possible obs: 92.9 % / Redundancy: 6.5 % / Rrim(I) all: 0.122 / Net I/σ(I): 10.9
Reflection shellResolution: 1.973→1.98 Å / Num. unique obs: 307 / Rrim(I) all: 1.662

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Processing

Software
NameVersionClassification
BUSTER2.11.8 (16-JUL-2021)refinement
XDSdata reduction
Aimlessdata scaling
BUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.973→47.05 Å / Cor.coef. Fo:Fc: 0.922 / Cor.coef. Fo:Fc free: 0.909 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.259 / SU Rfree Blow DPI: 0.204
Details: HYDROGENS WERE FULLY REFINED WITH FULL OCCUPANCY AT NUCLEAR POSITION.
RfactorNum. reflection% reflectionSelection details
Rfree0.2719 1359 4.99 %RANDOM
Rwork0.2265 ---
obs0.2288 27229 92.8 %-
Displacement parametersBiso mean: 40.36 Å2
Baniso -1Baniso -2Baniso -3
1--4.2454 Å20 Å2-4.9755 Å2
2--6.6229 Å20 Å2
3----2.3775 Å2
Refine analyzeLuzzati coordinate error obs: 0.28 Å
Refinement stepCycle: LAST / Resolution: 1.973→47.05 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3309 0 98 286 3693
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0126829HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0412241HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1503SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes1078HARMONIC16
X-RAY DIFFRACTIONt_it6829HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion6.94
X-RAY DIFFRACTIONt_other_torsion16.15
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion428SEMIHARMONIC5
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_contact5384SEMIHARMONIC4
LS refinement shellResolution: 1.973→1.99 Å
RfactorNum. reflection% reflection
Rfree0.3863 -4.04 %
Rwork0.3082 523 -
obs--100 %
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)
11.0913-0.03320.07481.4647-0.35680.38350.0896-0.06820.13590.0244-0.0640.08810.07930.0759-0.0256-0.1105-0.0179-0.0409-0.03320.00220.120220.6372-13.61524.1016
21.10490.5893-0.12852.12570.63691.3365-0.1069-0.1871-0.0525-0.025-0.07620.07890.02460.10960.1831-0.0026-0.0069-0.0618-0.0490.0205-0.0011.4968-21.467832.3461
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|11 - A|217 }
2X-RAY DIFFRACTION2{ B|11 - B|217 }

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