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- PDB-8qm8: Potential drug binding sites for translation initiation factor eIF4E -

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Basic information

Entry
Database: PDB / ID: 8qm8
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 / 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 / TRIETHYLENE GLYCOL / : / Eukaryotic translation initiation factor 4E
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 1.585 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)51,74714
Polymers50,0312
Non-polymers1,71612
Water7,224401
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3520 Å2
ΔGint22 kcal/mol
Surface area21160 Å2
MethodPISA
Unit cell
Length a, b, c (Å)40.418, 42.035, 64.728
Angle α, β, γ (deg.)90.00, 90.01, 117.22
Int Tables number1
Space group name H-MP1

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Eukaryotic translation initiation factor 4E


Mass: 25015.432 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, 413 molecules

#2: Chemical
ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C4H10O3
#3: Chemical ChemComp-PGE / TRIETHYLENE GLYCOL


Mass: 150.173 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H14O4
#4: 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
#5: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 401 / 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: 1.95 Å3/Da / Density % sol: 37.07 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8 / Details: 10% PEG 3350 0.1M pH=8 Bicine/NaOH

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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 EIGER R 1M / Detector: PIXEL / Date: Oct 18, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 1.585→64.73 Å / Num. obs: 36074 / % possible obs: 70.6 % / Redundancy: 3.6 % / Rrim(I) all: 0.06 / Net I/σ(I): 9.3
Reflection shellResolution: 1.585→1.59 Å / Num. unique obs: 23 / Rrim(I) all: 1.155

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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: 1.585→64.73 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.942 / SU R Cruickshank DPI: 0.219 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.133 / SU Rfree Blow DPI: 0.119 / SU Rfree Cruickshank DPI: 0.118
Details: HYDROGENS WERE FULLY REFINED WITH FULL OCCUPANCY AT NUCLEAR POSITION.
RfactorNum. reflection% reflectionSelection details
Rfree0.2017 1828 5.07 %RANDOM
Rwork0.1651 ---
obs0.1669 36072 70.1 %-
Displacement parametersBiso mean: 23.671 Å2
Baniso -1Baniso -2Baniso -3
1-0.4195 Å20.3629 Å2-0.2503 Å2
2--0.1738 Å2-0.2178 Å2
3----0.5933 Å2
Refine analyzeLuzzati coordinate error obs: 0.19 Å
Refinement stepCycle: LAST / Resolution: 1.585→64.73 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3344 0 114 401 3859
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0146951HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.112459HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1545SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes1099HARMONIC16
X-RAY DIFFRACTIONt_it6951HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion6.1
X-RAY DIFFRACTIONt_other_torsion14.87
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion432SEMIHARMONIC5
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_contact5883SEMIHARMONIC4
LS refinement shellResolution: 1.585→1.67 Å
RfactorNum. reflection% reflection
Rfree0.2753 -6.65 %
Rwork0.2697 674 -
obs--9.84 %
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)
10.41860.40720.18290.8022-0.27460.74360.0168-0.03480.0204-0.027-0.01290.08240.011-0.0131-0.0038-0.01520.0146-0.013-0.0036-0.0109-0.0172-5.1248-23.43583.2559
20.39880.3995-0.26020.75830.19220.73120.0067-0.0375-0.0287-0.0264-0.0102-0.0855-0.00780.00940.0034-0.0130.0150.0111-0.0030.0027-0.01748.5434-16.2339-29.2716
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|10 - A|217 }
2X-RAY DIFFRACTION2{ B|10 - B|217 }

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