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- PDB-9gax: TEAD1 in complex with a reversible inhibitor N-[(1S)-2-hydroxy-1-... -

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Basic information

Entry
Database: PDB / ID: 9gax
TitleTEAD1 in complex with a reversible inhibitor N-[(1S)-2-hydroxy-1-(1-methyl-1H-pyrazol-3-yl)ethyl]-2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indole-5-carboxamide
ComponentsTranscriptional enhancer factor TEF-1
KeywordsTRANSCRIPTION / IRREVERSIBLE COVALENT INHIBITOR / MESOTHELIOMA TUMOR REGRESSION / TRANSCRIPTION REGULATION / TRANSCRIPTION-PROTEIN BINDING COMPLEX
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 / regulation of transcription by RNA polymerase II / chromatin / 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
: / Transcriptional enhancer factor TEF-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.93 Å
AuthorsMusil, D. / Freire, F.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2025
Title: MoA Studies of the TEAD P-Site Binding Ligand MSC-4106 and Its Optimization to TEAD1-Selective Amide M3686.
Authors: Heinrich, T. / Schwarz, D. / Petersson, C. / Gunera, J. / Garg, S. / Schneider, R. / Keil, M. / Grimmeisen, L. / Unzue Lopez, A. / Albers, L. / Schlesiger, S. / Gambardella, A. / Bomke, J. / ...Authors: Heinrich, T. / Schwarz, D. / Petersson, C. / Gunera, J. / Garg, S. / Schneider, R. / Keil, M. / Grimmeisen, L. / Unzue Lopez, A. / Albers, L. / Schlesiger, S. / Gambardella, A. / Bomke, J. / Carswell, E. / Schilke, H. / Diehl, P. / Doerfel, B. / Musil, D. / Trivier, E. / Broome, R. / Marshall, S. / Balsiger, A. / Friedrich, E. / Lemos, A.R. / Santos, S.P. / Sousa, P.M.F. / Freire, F. / Bandeiras, T.M. / Bortoluzzi, A. / Wienke, D.
History
DepositionJul 29, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 22, 2025Provider: repository / Type: Initial release
Revision 1.1Apr 9, 2025Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)52,64712
Polymers50,9222
Non-polymers1,72510
Water3,909217
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3820 Å2
ΔGint-91 kcal/mol
Surface area20510 Å2
Unit cell
Length a, b, c (Å)107.995, 107.995, 132.202
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number92
Space group name H-MP41212
Components on special symmetry positions
IDModelComponents
11B-628-

HOH

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Components

#1: Protein Transcriptional enhancer factor TEF-1 / NTEF-1 / Protein GT-IIC / TEA domain family member 1 / TEAD-1 / Transcription factor 13 / TCF-13


Mass: 25460.971 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TEAD1, TCF13, TEF1 / Production host: Escherichia coli (E. coli) / References: UniProt: P28347
#2: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical ChemComp-A1IJL / 2-methyl-~{N}-[(1~{S})-1-(1-methylpyrazol-3-yl)-2-oxidanyl-ethyl]-4-[4-(trifluoromethyl)phenyl]pyrazolo[3,4-b]indole-7-carboxamide


Mass: 482.458 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H21F3N6O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 217 / Source method: isolated from a natural source / Formula: H2O
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: 3.78 Å3/Da / Density % sol: 67.5 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 3.5 M Ammonium sulfate, 1% (v/v) MPD, 0.1 M MES pH 6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID30B / Wavelength: 0.97625 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 26, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97625 Å / Relative weight: 1
ReflectionResolution: 1.928→83.636 Å / Num. obs: 48555 / % possible obs: 92.8 % / Redundancy: 8.9 % / CC1/2: 0.998 / Rpim(I) all: 0.055 / Rrim(I) all: 0.173 / Net I/σ(I): 9.8
Reflection shellResolution: 1.928→2.065 Å / Num. unique obs: 2429 / CC1/2: 0.633 / Rpim(I) all: 0.512

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Processing

Software
NameVersionClassification
PHENIX(1.20.1_4487: ???)refinement
XDSdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.93→28.19 Å / SU ML: 0.17 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 22.41 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2186 2349 4.84 %
Rwork0.186 --
obs0.1875 48534 81.6 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.93→28.19 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3539 0 112 217 3868
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.008
X-RAY DIFFRACTIONf_angle_d1.021
X-RAY DIFFRACTIONf_dihedral_angle_d6.139577
X-RAY DIFFRACTIONf_chiral_restr0.067547
X-RAY DIFFRACTIONf_plane_restr0.008662
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.01-2.060.3311580.25441304X-RAY DIFFRACTION40
2.06-2.110.27161000.24712428X-RAY DIFFRACTION73
2.11-2.160.27981540.23513070X-RAY DIFFRACTION93
2.16-2.230.24341790.23183210X-RAY DIFFRACTION99
2.23-2.30.23811180.22512041X-RAY DIFFRACTION62
2.3-2.380.2651490.21783287X-RAY DIFFRACTION100
2.38-2.480.25111560.20673327X-RAY DIFFRACTION100
2.48-2.590.2221930.2023299X-RAY DIFFRACTION100
2.59-2.730.22071980.19493281X-RAY DIFFRACTION100
2.73-2.90.23881680.19663313X-RAY DIFFRACTION100
2.9-3.120.22741620.19073346X-RAY DIFFRACTION100
3.12-3.430.19751630.16783366X-RAY DIFFRACTION100
3.44-3.930.20851620.15753203X-RAY DIFFRACTION95
3.93-4.950.18231620.14523430X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: 29.0744 Å / Origin y: 47.83 Å / Origin z: 8.4282 Å
111213212223313233
T0.1892 Å20.0075 Å20.0122 Å2-0.2083 Å2-0.029 Å2--0.1931 Å2
L0.6739 °20.211 °20.3104 °2-0.4955 °20.2182 °2--0.4704 °2
S-0.0163 Å °-0.011 Å °-0.0231 Å °0.0272 Å °0.0073 Å °0.0297 Å °-0.0342 Å °-0.0187 Å °0 Å °
Refinement TLS groupSelection details: all

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