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- PDB-8q68: Crystal structure of TEAD1-YBD in complex with irreversible compo... -

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Basic information

Entry
Database: PDB / ID: 8q68
TitleCrystal structure of TEAD1-YBD in complex with irreversible compound SWTX-143
ComponentsTranscriptional enhancer factor TEF-1
KeywordsTRANSCRIPTION / irreversible covalent inhibitor / mesothelioma tumor regression
Function / homology
Function and homology information


TEAD-YAP complex / RUNX3 regulates YAP1-mediated transcription / YAP1- and WWTR1 (TAZ)-stimulated gene expression / hippo signaling / EGR2 and SOX10-mediated initiation of Schwann cell myelination / embryonic organ development / positive regulation of miRNA transcription / sequence-specific double-stranded DNA binding / positive regulation of cell growth / protein-containing complex assembly ...TEAD-YAP complex / RUNX3 regulates YAP1-mediated transcription / YAP1- and WWTR1 (TAZ)-stimulated gene expression / hippo signaling / EGR2 and SOX10-mediated initiation of Schwann cell myelination / embryonic organ development / positive regulation of miRNA transcription / sequence-specific double-stranded DNA binding / positive regulation of cell growth / protein-containing complex assembly / transcription regulator complex / DNA-binding transcription factor activity, RNA polymerase II-specific / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / chromatin / regulation of transcription by RNA polymerase II / positive regulation of DNA-templated transcription / positive regulation of transcription by RNA polymerase II / DNA binding / nucleoplasm / nucleus
Similarity search - Function
TEA/ATTS domain / Transcriptional enhancer factor, metazoa / TEA/ATTS domain superfamily / TEA/ATTS domain / TEA domain signature. / TEA domain profile. / TEA domain / YAP binding domain / YAP binding domain
Similarity search - Domain/homology
Chem-K46 / Transcriptional enhancer factor TEF-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.58 Å
AuthorsCiesielski, F. / Spieser, S.A.H. / Marchand, A. / Gwaltney, S.L.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Mol.Cancer Ther. / Year: 2024
Title: A Novel Irreversible TEAD Inhibitor, SWTX-143, Blocks Hippo Pathway Transcriptional Output and Causes Tumor Regression in Preclinical Mesothelioma Models.
Authors: Hillen, H. / Candi, A. / Vanderhoydonck, B. / Kowalczyk, W. / Sansores-Garcia, L. / Kesikiadou, E.C. / Van Huffel, L. / Spiessens, L. / Nijs, M. / Soons, E. / Haeck, W. / Klaassen, H. / ...Authors: Hillen, H. / Candi, A. / Vanderhoydonck, B. / Kowalczyk, W. / Sansores-Garcia, L. / Kesikiadou, E.C. / Van Huffel, L. / Spiessens, L. / Nijs, M. / Soons, E. / Haeck, W. / Klaassen, H. / Smets, W. / Spieser, S.A. / Marchand, A. / Chaltin, P. / Ciesielski, F. / Debaene, F. / Chen, L. / Kamal, A. / Gwaltney, S.L. / Versele, M. / Halder, G.A.
History
DepositionAug 11, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 4, 2023Provider: repository / Type: Initial release
Revision 1.1Jan 17, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation.year / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Transcriptional enhancer factor TEF-1
B: Transcriptional enhancer factor TEF-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,9454
Polymers55,2192
Non-polymers7272
Water5,134285
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: mass spectrometry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1910 Å2
ΔGint1 kcal/mol
Surface area20960 Å2
MethodPISA
Unit cell
Length a, b, c (Å)36.646, 89.726, 136.27
Angle α, β, γ (deg.)90, 90, 90
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Transcriptional enhancer factor TEF-1


Mass: 27609.367 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TEAD1 / Production host: Escherichia coli (E. coli) / References: UniProt: P28347
#2: Chemical ChemComp-K46 / ~{N}-[(3~{S})-5-azanyl-1-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2~{H}-quinolin-3-yl]propanamide


Mass: 363.377 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H20F3N3O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 285 / 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: 2.03 Å3/Da / Density % sol: 39.37 %
Crystal growTemperature: 295 K / Method: vapor diffusion / pH: 4.2
Details: 100mM phosphate citrate pH4.2, 10% glycerol, 25% 1,2-propanediol and 5% PEG3000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SOLEIL / Beamline: PROXIMA 2 / Wavelength: 0.9801 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Jun 9, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9801 Å / Relative weight: 1
ReflectionResolution: 1.58→74.94 Å / Num. obs: 34809 / % possible obs: 84 % / Redundancy: 5.23 %
Details: Some remarks regarding the mmCIF items written, the PDB Exchange Dictionary (PDBx/mmCIF) Version 5.0 supporting the data files in the current PDB archive (dictionary version 5.325, last ...Details: Some remarks regarding the mmCIF items written, the PDB Exchange Dictionary (PDBx/mmCIF) Version 5.0 supporting the data files in the current PDB archive (dictionary version 5.325, last updated 2020-04-13: http://mmcif.wwpdb.org/dictionaries/mmcif_pdbx_v50.dic/Index/) and the actual quantities provided by MRFANA (https://github.com/githubgphl/MRFANA) from the autoPROC package (https://www.globalphasing.com/autoproc/). In general, the mmCIF categories here should provide items that are currently used in the PDB archive. If there are alternatives, the one recommended by the PDB developers has been selected. The distinction between *_all and *_obs quantities is not always clear: often only one version is actively used within the PDB archive (or is the one recommended by PDB developers). The intention of distinguishing between classes of reflections before and after some kind of observation criterion was applied, can in principle be useful - but such criteria change in various ways throughout the data processing steps (rejection of overloaded or too partial reflections, outlier/misfit rejections during scaling etc) and there is no retrospect computation of data scaling/merging statistics for the reflections used in the final refinement (where another observation criterion might have been applied). Typical data processing will usually only provide one version of statistics at various stages and these are given in the recommended item here, irrespective of the "_all" and "_obs" connotation, see e.g. the use of _reflns.pdbx_Rmerge_I_obs, _reflns.pdbx_Rrim_I_all and _reflns.pdbx_Rpim_I_all. Please note that all statistics related to "merged intensities" (or "merging") are based on inverse-variance weighting of the individual measurements making up a symmetry-unique reflection. This is standard for several decades now, even if some of the dictionary definitions seem to suggest that a simple "mean" or "average" intensity is being used instead. R-values are always given for all symmetry-equivalent reflections following Friedel's law, i.e. Bijvoet pairs are not treated separately (since we want to describe the overall mean intensity and not the mean I(+) and I(-) here). The Rrim metric is identical to the Rmeas R-value and only differs in name. _reflns.pdbx_number_measured_all is the number of measured intensities just before the final merging step (at which point no additional rejection takes place). _reflns.number_obs is the number of symmetry-unique observations, i.e. the result of merging those measurements via inverse-variance weighting. _reflns.pdbx_netI_over_sigmaI is based on the merged intensities (_reflns.number_obs) as expected. _reflns.pdbx_redundancy is synonymous with "multiplicity". The per-shell item _reflns_shell.number_measured_all corresponds to the overall value _reflns.pdbx_number_measured_all. The per-shell item _reflns_shell.number_unique_all corresponds to the overall value _reflns.number_obs. The per-shell item _reflns_shell.percent_possible_all corresponds to the overall value _reflns.percent_possible_obs. The per-shell item _reflns_shell.meanI_over_sigI_obs corresponds to the overall value given as _reflns.pdbx_netI_over_sigmaI. But be aware of the incorrect definition of the former in the current dictionary!
CC1/2: 0.997 / CC1/2 anomalous: -0.043 / Rmerge(I) obs: 0.1363 / Rpim(I) all: 0.0648 / Rrim(I) all: 0.1515 / AbsDiff over sigma anomalous: 0.789 / Baniso tensor eigenvalue 1: 14.6 Å2 / Baniso tensor eigenvalue 2: 38.7 Å2 / Baniso tensor eigenvalue 3: 20.5 Å2 / Baniso tensor eigenvector 1 ortho1: 1 / Baniso tensor eigenvector 1 ortho2: 0 / Baniso tensor eigenvector 1 ortho3: 0 / Baniso tensor eigenvector 2 ortho1: 0 / Baniso tensor eigenvector 2 ortho2: 1 / Baniso tensor eigenvector 2 ortho3: 0 / Baniso tensor eigenvector 3 ortho1: 0 / Baniso tensor eigenvector 3 ortho2: 0 / Baniso tensor eigenvector 3 ortho3: 1 / Aniso diffraction limit 1: 1.58 Å / Aniso diffraction limit 2: 2.192 Å / Aniso diffraction limit 3: 1.754 Å / Aniso diffraction limit axis 1 ortho1: 1 / Aniso diffraction limit axis 1 ortho2: 0 / Aniso diffraction limit axis 1 ortho3: 0 / Aniso diffraction limit axis 2 ortho1: 0 / Aniso diffraction limit axis 2 ortho2: 1 / Aniso diffraction limit axis 2 ortho3: 0 / Aniso diffraction limit axis 3 ortho1: 0 / Aniso diffraction limit axis 3 ortho2: 0 / Aniso diffraction limit axis 3 ortho3: 1 / Net I/σ(I): 8.68 / Num. measured all: 182072 / Observed signal threshold: 1.2 / Orthogonalization convention: pdb / % possible anomalous: 80.4 / % possible ellipsoidal: 84 / % possible ellipsoidal anomalous: 80.4 / % possible spherical: 55.6 / % possible spherical anomalous: 52.6 / Redundancy anomalous: 2.83 / Signal type: local
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. measured obsNum. unique allNum. unique obsCC1/2CC1/2 anomalousRpim(I) allRrim(I) allAbsDiff over sigma anomalous% possible anomalous% possible ellipsoidal% possible ellipsoidal anomalous% possible spherical% possible spherical anomalousRedundancy anomalous% possible all
5.379-74.944.750.046922.7583278327175317530.9980.0580.02280.05250.67394.89994.89994.82.8999
4.238-5.3794.880.0523.9285028502174317430.997-0.1190.02390.05580.69895.599.395.599.395.52.7899.3
3.626-4.2384.570.060220.2580008000175017500.996-0.0420.030.06760.77884.888.384.888.384.82.5488.3
3.26-3.6264.920.079417.2185528552173917390.995-0.1280.0390.08890.8182.286.482.286.482.22.7286.4
3.03-3.264.710.100213.6681858185173717370.993-0.1290.05090.1130.79395.39995.39995.32.5999
2.855-3.034.780.139911.2783098309173817380.985-0.0070.07010.15730.8193.498.893.498.893.42.6398.8
2.716-2.8555.060.18379.4887918791173717370.979-00.09080.2060.83195.499.595.499.595.42.7599.5
2.535-2.7165.020.2397.6787548754174417440.9670.0090.11720.26760.78857.861.357.861.357.82.7561.3
2.439-2.5355.420.30486.7794239423173717370.96-0.0160.14350.33830.8048993.28993.2892.9293.2
2.355-2.4395.50.31866.6595569556173717370.9590.0450.14820.35280.81187.891.287.891.287.82.9691.2
2.278-2.3555.670.35866.0398379837173617360.96-0.0260.16270.39510.82385.388.585.388.585.33.0388.5
2.176-2.2785.250.45414.7192059205175217520.93-0.0060.2120.50330.79454.657.554.657.354.52.8457.5
2.118-2.1765.650.50294.5898239823173817380.919-0.0060.23070.55510.80486.389.486.384.482.42.9989.4
2.063-2.1185.070.54793.8888078807173717370.888-0.0260.26750.6120.80290.193.690.182.480.22.6993.6
2.012-2.0635.430.68993.394359435173717370.846-0.0220.32210.76390.7779396.59379.978.12.8796.5
1.964-2.0125.580.82622.9797119711173917390.787-0.0390.37590.91040.78392.696.992.676.374.22.9596.9
1.916-1.9645.760.84762.7699979997173717370.783-0.0230.37950.93130.77691.695.291.669.968.43.0395.2
1.867-1.9165.791.10542.091008010080174017400.665-0.0060.48971.21230.79291.193.591.161.4613.0293.5
1.808-1.8675.781.2611.821005310053174017400.606-0.0130.55951.38320.88484.98446.346.33.0184.9
1.58-1.8085.021.18691.6687258725173817380.5660.0340.56971.32240.80843.44543.48.58.12.6345

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Processing

Software
NameVersionClassification
BUSTER2.11.8 (8-JUN-2022)refinement
PHASERphasing
STARANISO2.3.77data scaling
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.58→74.94 Å / Cor.coef. Fo:Fc: 0.935 / Cor.coef. Fo:Fc free: 0.908 / SU R Cruickshank DPI: 0.183 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.194 / SU Rfree Blow DPI: 0.172 / SU Rfree Cruickshank DPI: 0.168
RfactorNum. reflection% reflectionSelection details
Rfree0.2604 1719 -RANDOM
Rwork0.2087 ---
obs0.2113 34809 55.5 %-
Displacement parametersBiso mean: 23.49 Å2
Baniso -1Baniso -2Baniso -3
1-1.0044 Å20 Å20 Å2
2---0.9662 Å20 Å2
3----0.0382 Å2
Refine analyzeLuzzati coordinate error obs: 0.27 Å
Refinement stepCycle: LAST / Resolution: 1.58→74.94 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3462 0 52 285 3799
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.013787HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.115144HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1364SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes687HARMONIC5
X-RAY DIFFRACTIONt_it3787HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion470SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact3319SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion3.89
X-RAY DIFFRACTIONt_other_torsion15.75
LS refinement shellResolution: 1.58→1.75 Å
RfactorNum. reflection% reflection
Rfree0.3436 38 -
Rwork0.2458 --
obs0.2512 697 4.3 %

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