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- PDB-7meu: A biphenyl inhibitor of eIF4E targeting an internal binding site ... -

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Basic information

Entry
Database: PDB / ID: 7meu
TitleA biphenyl inhibitor of eIF4E targeting an internal binding site enables the design of cell-permeable PROTAC-degraders
ComponentsEukaryotic translation initiation factor 4EEIF4E
KeywordsPROTEIN BINDING / Inhibitor / Complex / 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 / 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 / mRNA cap binding / : / Deadenylation of mRNA ...Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43S / eukaryotic initiation factor 4G binding / 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 / 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 / Ribosomal scanning and start codon recognition / Translation initiation complex formation / stem cell population maintenance / mTORC1-mediated signalling / GTP hydrolysis and joining of the 60S ribosomal subunit / negative regulation of neuron differentiation / L13a-mediated translational silencing of Ceruloplasmin expression / behavioral fear response / mRNA export from nucleus / translational initiation / translation initiation factor activity / cellular response to dexamethasone stimulus / positive regulation of mitotic cell cycle / P-body / G1/S transition of mitotic cell cycle / cytoplasmic ribonucleoprotein granule / ISG15 antiviral mechanism / neuron differentiation / cytoplasmic stress granule / 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 / 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
7-METHYL-GUANOSINE-5'-TRIPHOSPHATE / Chem-Z5D / Eukaryotic translation initiation factor 4E
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.91 Å
AuthorsPapadopoulos, E.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI) United States
CitationJournal: Eur.J.Med.Chem. / Year: 2021
Title: A biphenyl inhibitor of eIF4E targeting an internal binding site enables the design of cell-permeable PROTAC-degraders.
Authors: Fischer, P.D. / Papadopoulos, E. / Dempersmier, J.M. / Wang, Z.F. / Nowak, R.P. / Donovan, K.A. / Kalabathula, J. / Gorgulla, C. / Junghanns, P.P.M. / Kabha, E. / Dimitrakakis, N. / Petrov, ...Authors: Fischer, P.D. / Papadopoulos, E. / Dempersmier, J.M. / Wang, Z.F. / Nowak, R.P. / Donovan, K.A. / Kalabathula, J. / Gorgulla, C. / Junghanns, P.P.M. / Kabha, E. / Dimitrakakis, N. / Petrov, O.I. / Mitsiades, C. / Ducho, C. / Gelev, V. / Fischer, E.S. / Wagner, G. / Arthanari, H.
History
DepositionApr 7, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 28, 2021Provider: repository / Type: Initial release
Revision 1.1May 5, 2021Group: 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_author.name
Revision 1.2Oct 18, 2023Group: 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

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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)46,3745
Polymers44,8392
Non-polymers1,5353
Water4,972276
1
A: Eukaryotic translation initiation factor 4E
hetero molecules


Theoretical massNumber of molelcules
Total (without water)23,4163
Polymers22,4191
Non-polymers9972
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Eukaryotic translation initiation factor 4E
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,9582
Polymers22,4191
Non-polymers5381
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)38.812, 73.364, 61.866
Angle α, β, γ (deg.)90.000, 101.360, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

#1: Protein Eukaryotic translation initiation factor 4E / EIF4E / eIF-4E / eIF4E / eIF-4F 25 kDa subunit / mRNA cap-binding protein


Mass: 22419.451 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EIF4E, EIF4EL1, EIF4F / Production host: Escherichia coli (E. coli) / References: UniProt: P06730
#2: Chemical ChemComp-MGP / 7-METHYL-GUANOSINE-5'-TRIPHOSPHATE


Mass: 538.215 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C11H19N5O14P3
#3: Chemical ChemComp-Z5D / (2E)-2-{2-[4-([1,1'-biphenyl]-4-yl)-1,3-thiazol-2-yl]hydrazinylidene}-3-(2-nitrophenyl)propanoic acid


Mass: 458.489 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H18N4O4S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 276 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 1.93 Å3/Da / Density % sol: 36.13 %
Crystal growTemperature: 290 K / Method: vapor diffusion, sitting drop / pH: 6.5 / Details: PEG 4000 10-20%, 100mM MES pH 6.5, 10% IPN

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Data collection

DiffractionMean temperature: 290 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.97918 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Feb 13, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 1.91→60.65 Å / Num. obs: 25424 / % possible obs: 96.64 % / Redundancy: 3.411 % / Biso Wilson estimate: 17.85 Å2 / Rmerge(I) obs: 0.05771 / Rpim(I) all: 0.03603 / Net I/σ(I): 18.94
Reflection shellResolution: 1.914→1.983 Å / Num. unique obs: 1853 / CC1/2: 0.997

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Processing

Software
NameVersionClassification
PHENIX1.18.2_3874refinement
HKL-2000data reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4TPW

4tpw


Resolution: 1.91→60.65 Å / SU ML: 0.2061 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 22.5491
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2187 2000 7.87 %
Rwork0.161 23417 -
obs0.1656 25417 96.64 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 25.39 Å2
Refinement stepCycle: LAST / Resolution: 1.91→60.65 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3034 0 99 276 3409
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.02053312
X-RAY DIFFRACTIONf_angle_d2.01174518
X-RAY DIFFRACTIONf_chiral_restr0.0787459
X-RAY DIFFRACTIONf_plane_restr0.0125568
X-RAY DIFFRACTIONf_dihedral_angle_d31.3282515
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.91-1.960.3214930.24931093X-RAY DIFFRACTION63.02
1.96-2.020.2741380.21041616X-RAY DIFFRACTION94.05
2.02-2.070.26291480.17471727X-RAY DIFFRACTION100
2.07-2.140.22251480.16111731X-RAY DIFFRACTION99.95
2.14-2.220.2231450.16561704X-RAY DIFFRACTION100
2.22-2.310.22961480.15391727X-RAY DIFFRACTION99.89
2.31-2.410.22591480.16171730X-RAY DIFFRACTION100
2.41-2.540.23821460.15381709X-RAY DIFFRACTION99.95
2.54-2.70.22181460.15871724X-RAY DIFFRACTION99.84
2.7-2.910.21911480.15781729X-RAY DIFFRACTION100
2.91-3.20.23341490.15521742X-RAY DIFFRACTION99.84
3.2-3.660.2221460.15061712X-RAY DIFFRACTION99.36
3.66-4.610.16811480.1361723X-RAY DIFFRACTION99.31
4.61-60.650.21490.17891750X-RAY DIFFRACTION98.04

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