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- PDB-7zjp: Optimization of TEAD P-Site Binding Fragment Hit into In Vivo Act... -

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Basic information

Entry
Database: PDB / ID: 7zjp
TitleOptimization of TEAD P-Site Binding Fragment Hit into In Vivo Active Lead MSC-4106
ComponentsTranscriptional enhancer factor TEF-1
KeywordsTRANSCRIPTION / IMMUNOGLOBULIN-LIKE FOLD / ACTIVATOR / DISEASE MUTATION / DNA-BINDING / NUCLEUS / PHOSPHOPROTEIN / 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 / DNA-binding transcription factor activity / RNA polymerase II cis-regulatory region sequence-specific DNA binding / 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-JJU / Transcriptional enhancer factor TEF-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.19 Å
AuthorsFreire, F. / Heinrich, T. / Petersson, C. / Schneider, R. / Garg, S. / Schwarz, D. / Gunera, J. / Seshire, A. / Koetzner, L. / Schlesiger, S. ...Freire, F. / Heinrich, T. / Petersson, C. / Schneider, R. / Garg, S. / Schwarz, D. / Gunera, J. / Seshire, A. / Koetzner, L. / Schlesiger, S. / Musil, D. / Schilke, H. / Doerfel, B. / Diehl, P. / Boepple, P. / Lemos, A.R. / Sousa, P.M.F. / Freire, F. / Bandeiras, T.M. / Carswell, E. / Pearson, N. / Sirohi, S. / Hooker, M. / Trivier, E. / Broome, R. / Balsiger, A. / Crowden, A. / Dillon, C. / Wienke, D.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2022
Title: Optimization of TEAD P-Site Binding Fragment Hit into In Vivo Active Lead MSC-4106 .
Authors: Heinrich, T. / Peterson, C. / Schneider, R. / Garg, S. / Schwarz, D. / Gunera, J. / Seshire, A. / Kotzner, L. / Schlesiger, S. / Musil, D. / Schilke, H. / Doerfel, B. / Diehl, P. / Bopple, P. ...Authors: Heinrich, T. / Peterson, C. / Schneider, R. / Garg, S. / Schwarz, D. / Gunera, J. / Seshire, A. / Kotzner, L. / Schlesiger, S. / Musil, D. / Schilke, H. / Doerfel, B. / Diehl, P. / Bopple, P. / Lemos, A.R. / Sousa, P.M.F. / Freire, F. / Bandeiras, T.M. / Carswell, E. / Pearson, N. / Sirohi, S. / Hooker, M. / Trivier, E. / Broome, R. / Balsiger, A. / Crowden, A. / Dillon, C. / Wienke, D.
History
DepositionApr 11, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 13, 2022Provider: repository / Type: Initial release
Revision 1.1Jul 27, 2022Group: 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_author.identifier_ORCID
Revision 1.2Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)51,9297
Polymers50,9222
Non-polymers1,0075
Water1,51384
1
A: Transcriptional enhancer factor TEF-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)26,0124
Polymers25,4611
Non-polymers5513
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Transcriptional enhancer factor TEF-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,9163
Polymers25,4611
Non-polymers4552
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)108.359, 108.359, 132.162
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212

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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 BL21(DE3) (bacteria) / Variant (production host): Star / References: UniProt: P28347
#2: Chemical ChemComp-JJU / 2-methyl-4-[4-(trifluoromethyl)phenyl]pyrazolo[3,4-b]indole-7-carboxylic acid


Mass: 359.302 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H12F3N3O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 84 / 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: 3.81 Å3/Da / Density % sol: 67.71 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 8.5 / Details: 2.2 M Ammonium Sulfate 20 % w/v Glycerol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.999909 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: May 15, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.999909 Å / Relative weight: 1
ReflectionResolution: 2.19→83.8 Å / Num. obs: 30690 / % possible obs: 74.7 % / Redundancy: 13.1 % / CC1/2: 0.999 / Rpim(I) all: 0.038 / Net I/σ(I): 15.3
Reflection shellResolution: 2.19→2.39 Å / Num. unique obs: 1535 / CC1/2: 0.566 / Rpim(I) all: 0.557

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Processing

Software
NameVersionClassification
BUSTER2.10.3refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
autoPROCdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3KYS

3kys


Resolution: 2.19→27.93 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.921 / SU R Cruickshank DPI: 0.218 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.219 / SU Rfree Blow DPI: 0.195 / SU Rfree Cruickshank DPI: 0.196
RfactorNum. reflection% reflectionSelection details
Rfree0.236 1497 4.88 %RANDOM
Rwork0.19 ---
obs0.193 30662 74.7 %-
Displacement parametersBiso max: 140.94 Å2 / Biso mean: 60.09 Å2 / Biso min: 29.18 Å2
Baniso -1Baniso -2Baniso -3
1-0.6358 Å20 Å20 Å2
2--0.6358 Å20 Å2
3----1.2717 Å2
Refine analyzeLuzzati coordinate error obs: 0.3 Å
Refinement stepCycle: final / Resolution: 2.19→27.93 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3487 0 67 84 3638
Biso mean--61.67 58.52 -
Num. residues----428
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1290SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes619HARMONIC5
X-RAY DIFFRACTIONt_it3656HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion449SEMIHARMONIC5
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_contact3957SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d3656HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg4937HARMONIC21.13
X-RAY DIFFRACTIONt_omega_torsion3.47
X-RAY DIFFRACTIONt_other_torsion19.6
LS refinement shellResolution: 2.19→2.31 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.225 24 3.91 %
Rwork-590 -
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)
12.5060.05430.45261.66350.07971.6794-0.0887-0.06-0.06270.03010.03950.1328-0.0656-0.28410.0491-0.08660.00950.0254-0.0934-0.0413-0.107316.218241.39670.6163
21.02330.31210.09441.23570.51941.661-0.091-0.07480.09390.04020.0198-0.0395-0.204-0.04330.0712-0.0681-0.01-0.044-0.0515-0.0911-0.080842.297954.198215.3515
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A207 - 426
2X-RAY DIFFRACTION2{ B|* }B209 - 426

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