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- PDB-5mwj: Structure Enabled Discovery of a Stapled Peptide Inhibitor to Tar... -

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Basic information

Entry
Database: PDB / ID: 5mwj
TitleStructure Enabled Discovery of a Stapled Peptide Inhibitor to Target the Oncogenic Transcriptional Repressor TLE1
ComponentsTransducin-like enhancer protein 1
KeywordsTRANSCRIPTION / Transducin-like / Constrained peptide inhibitor / Transcriptional corepressor
Function / homology
Function and homology information


Repression of WNT target genes / beta-catenin-TCF complex / negative regulation of Wnt signaling pathway / negative regulation of anoikis / negative regulation of canonical NF-kappaB signal transduction / animal organ morphogenesis / Deactivation of the beta-catenin transactivating complex / Formation of the beta-catenin:TCF transactivating complex / negative regulation of canonical Wnt signaling pathway / NOTCH1 Intracellular Domain Regulates Transcription ...Repression of WNT target genes / beta-catenin-TCF complex / negative regulation of Wnt signaling pathway / negative regulation of anoikis / negative regulation of canonical NF-kappaB signal transduction / animal organ morphogenesis / Deactivation of the beta-catenin transactivating complex / Formation of the beta-catenin:TCF transactivating complex / negative regulation of canonical Wnt signaling pathway / NOTCH1 Intracellular Domain Regulates Transcription / Wnt signaling pathway / transcription corepressor activity / DNA-binding transcription factor binding / transcription regulator complex / negative regulation of DNA-templated transcription / positive regulation of gene expression / signal transduction / nucleoplasm / identical protein binding / nucleus / cytosol
Similarity search - Function
Groucho/TLE, N-terminal Q-rich domain / Groucho/TLE N-terminal Q-rich domain / Groucho/transducin-like enhancer / YVTN repeat-like/Quinoprotein amine dehydrogenase / 7 Propeller / Methylamine Dehydrogenase; Chain H / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / WD domain, G-beta repeat / Trp-Asp (WD) repeats profile. ...Groucho/TLE, N-terminal Q-rich domain / Groucho/TLE N-terminal Q-rich domain / Groucho/transducin-like enhancer / YVTN repeat-like/Quinoprotein amine dehydrogenase / 7 Propeller / Methylamine Dehydrogenase; Chain H / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / WD domain, G-beta repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / Mainly Beta
Similarity search - Domain/homology
pepide inhibtor / Transducin-like enhancer protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.04 Å
AuthorsMcGrath, S. / Tortorici, M. / Vidler, L. / Drouin, L. / Westwood, I. / Gimeson, P. / Van Montfort, R. / Hoelder, S.
CitationJournal: Chemistry / Year: 2017
Title: Structure-Enabled Discovery of a Stapled Peptide Inhibitor to Target the Oncogenic Transcriptional Repressor TLE1.
Authors: McGrath, S. / Tortorici, M. / Drouin, L. / Solanki, S. / Vidler, L. / Westwood, I. / Gimeson, P. / Van Montfort, R. / Hoelder, S.
History
DepositionJan 18, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 5, 2017Provider: repository / Type: Initial release
Revision 1.1Jul 26, 2017Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_volume ..._citation.country / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.name
Revision 1.2Oct 10, 2018Group: Data collection / Source and taxonomy / Structure summary
Category: entity / entity_src_gen
Item: _entity.formula_weight / _entity_src_gen.pdbx_host_org_cell_line ..._entity.formula_weight / _entity_src_gen.pdbx_host_org_cell_line / _entity_src_gen.pdbx_host_org_ncbi_taxonomy_id / _entity_src_gen.pdbx_host_org_scientific_name / _entity_src_gen.pdbx_host_org_vector
Revision 1.3Oct 17, 2018Group: Data collection / Source and taxonomy / Category: entity_src_gen / Item: _entity_src_gen.pdbx_host_org_scientific_name
Revision 1.4Oct 16, 2019Group: Data collection / Structure summary / Category: entity / reflns_shell / Item: _entity.formula_weight
Revision 1.5Jan 17, 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: Transducin-like enhancer protein 1
B: Transducin-like enhancer protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,4755
Polymers73,7072
Non-polymers1,7683
Water3,099172
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2470 Å2
ΔGint-12 kcal/mol
Surface area24380 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.940, 57.000, 104.140
Angle α, β, γ (deg.)90.00, 103.01, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Transducin-like enhancer protein 1 / E(Sp1) homolog / Enhancer of split groucho-like protein 1 / ESG1


Mass: 36853.469 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TLE1 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q04724
#2: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#3: Chemical ChemComp-EBU / pepide inhibtor


Mass: 845.000 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C46H56N10O6
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 172 / Source method: isolated from a natural source / Formula: H2O

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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: 2.31 Å3/Da / Density % sol: 46.81 %
Crystal growTemperature: 293.15 K / Method: microbatch / pH: 8
Details: PEG 8000 (22%), 100mM sodium cacodylate, 100 mM Ca(OAc)2

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9795 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Feb 24, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.04→57 Å / Num. obs: 41686 / % possible obs: 96.7 % / Redundancy: 3 % / Biso Wilson estimate: 33.33 Å2 / CC1/2: 0.99 / Net I/σ(I): 5

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Processing

Software
NameVersionClassification
BUSTER2.10.2refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1GXR

1gxr


Resolution: 2.04→43.14 Å / Cor.coef. Fo:Fc: 0.957 / Cor.coef. Fo:Fc free: 0.947 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.188 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.185 / SU Rfree Blow DPI: 0.154 / SU Rfree Cruickshank DPI: 0.157
RfactorNum. reflection% reflectionSelection details
Rfree0.219 2024 4.86 %RANDOM
Rwork0.188 ---
obs0.19 41673 96.6 %-
Displacement parametersBiso mean: 55.24 Å2
Baniso -1Baniso -2Baniso -3
1--4.8349 Å20 Å2-1.0564 Å2
2--0.5882 Å20 Å2
3---4.2468 Å2
Refine analyzeLuzzati coordinate error obs: 0.31 Å
Refinement stepCycle: 1 / Resolution: 2.04→43.14 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4764 0 122 172 5058
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.015010HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.26848HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1593SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes97HARMONIC2
X-RAY DIFFRACTIONt_gen_planes804HARMONIC5
X-RAY DIFFRACTIONt_it5010HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.68
X-RAY DIFFRACTIONt_other_torsion17.68
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion666SEMIHARMONIC5
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_contact5511SEMIHARMONIC4
LS refinement shellResolution: 2.04→2.09 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.275 128 5.03 %
Rwork0.26 2417 -
all0.26 2545 -
obs--81.06 %
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)
12.0895-0.91750.32342.0317-1.05665.7292-0.16150.002-0.2570.1599-0.0592-0.1013-0.1711-0.01910.2208-0.021-0.03620.1587-0.304-0.02560.021669.7395-3.922144.668
23.6307-1.5258-1.96262.47440.87673.8925-0.1696-0.6225-0.06570.52430.23740.009-0.35820.2766-0.06780.16820.03140.2262-0.20230.0767-0.065560.18421.031263.8251
35.4295-0.2419-1.70580.63510.79790.1492-0.0276-0.19020.02880.09940.0293-0.0247-0.0227-0.2165-0.00170.18390.15130.21970.00350.0205-0.023246.7515.989657.0691
42.8591-0.0896-0.75792.0745-0.16064.2648-0.0030.128-0.2670.0909-0.01010.1214-0.2958-0.37360.0130.03480.00930.1789-0.2192-0.0373-0.005260.6414-0.762742.4756
51.7780.60560.46042.31072.30874.5446-0.0611-0.15890.0387-0.5289-0.033-0.0658-0.34140.05240.09410.23970.01670.1876-0.3040.0191-0.116366.0184-4.21929.2543
63.99631.3449-1.1791.4031-0.48214.4086-0.13770.49220.2006-0.40160.03430.11810.22080.28730.10340.23760.02550.2062-0.30170.0108-0.237671.1051-6.4644-14.4384
72.25-0.408-0.94072.21810.66352.89940.1056-0.00380.1872-0.48290.0341-0.3116-0.19510.4612-0.13970.2074-0.03440.2659-0.2754-0.0013-0.188977.3881-2.0164.9419
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{A|435 - 532}
2X-RAY DIFFRACTION2{A|533 - 635}
3X-RAY DIFFRACTION3{A|636 - 652}
4X-RAY DIFFRACTION4{A|653 - 770}
5X-RAY DIFFRACTION5{B|435 - 511}
6X-RAY DIFFRACTION6{B|512 - 612}
7X-RAY DIFFRACTION7{B|613 - 770}

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