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- PDB-9fza: TEAD1/YAP in complex with a reversible inhibitor N-[(4-phenoxyphe... -

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Basic information

Entry
Database: PDB / ID: 9fza
TitleTEAD1/YAP in complex with a reversible inhibitor N-[(4-phenoxyphenyl)methyl]imidazo[1,2-a]pyridine-3-carboxamide
Components
  • Transcriptional coactivator YAP1
  • Transcriptional enhancer factor TEF-1
KeywordsTRANSCRIPTION / IRREVERSIBLE COVALENT INHIBITOR / MESOTHELIOMA TUMOR REGRESSION / TRANSCRIPTION REGULATION / TRANSCRIPTION-PROTEIN BINDING COMPLEX
Function / homology
Function and homology information


enterocyte differentiation / regulation of keratinocyte proliferation / glandular epithelial cell differentiation / regulation of metanephric nephron tubule epithelial cell differentiation / cardiac muscle tissue regeneration / TEAD-YAP complex / lateral mesoderm development / bud elongation involved in lung branching / polarized epithelial cell differentiation / RUNX3 regulates YAP1-mediated transcription ...enterocyte differentiation / regulation of keratinocyte proliferation / glandular epithelial cell differentiation / regulation of metanephric nephron tubule epithelial cell differentiation / cardiac muscle tissue regeneration / TEAD-YAP complex / lateral mesoderm development / bud elongation involved in lung branching / polarized epithelial cell differentiation / RUNX3 regulates YAP1-mediated transcription / notochord development / negative regulation of cilium assembly / lung epithelial cell differentiation / YAP1- and WWTR1 (TAZ)-stimulated gene expression / heart process / trophectodermal cell differentiation / paraxial mesoderm development / hippo signaling / regulation of stem cell proliferation / negative regulation of epithelial cell apoptotic process / EGR2 and SOX10-mediated initiation of Schwann cell myelination / tissue homeostasis / intestinal epithelial cell development / Formation of axial mesoderm / negative regulation of stem cell differentiation / embryonic heart tube morphogenesis / female germ cell nucleus / Signaling by Hippo / proline-rich region binding / Differentiation of Keratinocytes in Interfollicular Epidermis in Mammalian Skin / organ growth / negative regulation of epithelial cell differentiation / interleukin-6-mediated signaling pathway / positive regulation of Notch signaling pathway / negative regulation of fat cell differentiation / RUNX2 regulates osteoblast differentiation / positive regulation of stem cell population maintenance / Zygotic genome activation (ZGA) / somatic stem cell population maintenance / regulation of neurogenesis / bicellular tight junction / canonical Wnt signaling pathway / embryonic organ development / positive regulation of osteoblast differentiation / vasculogenesis / Nuclear signaling by ERBB4 / keratinocyte differentiation / positive regulation of cardiac muscle cell proliferation / extrinsic apoptotic signaling pathway / cellular response to retinoic acid / response to progesterone / positive regulation of epithelial cell proliferation / Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells / epithelial cell proliferation / negative regulation of extrinsic apoptotic signaling pathway / transcription coregulator activity / wound healing / cellular response to gamma radiation / cell morphogenesis / positive regulation of miRNA transcription / positive regulation of protein localization to nucleus / sequence-specific double-stranded DNA binding / transcription corepressor activity / cell junction / positive regulation of canonical Wnt signaling pathway / cell-cell junction / RUNX1 regulates transcription of genes involved in differentiation of HSCs / DNA-binding transcription activator activity, RNA polymerase II-specific / positive regulation of cell growth / protein-containing complex assembly / transcription regulator complex / DNA-binding transcription factor binding / DNA-binding transcription factor activity, RNA polymerase II-specific / transcription coactivator activity / transcription cis-regulatory region binding / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / negative regulation of gene expression / DNA damage response / chromatin binding / positive regulation of gene expression / regulation of transcription by RNA polymerase II / chromatin / positive regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / positive regulation of transcription by RNA polymerase II / mitochondrion / DNA binding / nucleoplasm / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
: / Omega loop, TEAD interating region 3 / : / TEA/ATTS domain / Transcriptional enhancer factor, metazoa / TEA/ATTS domain superfamily / TEA/ATTS domain / TEA domain signature. / TEA domain profile. / TEA domain ...: / Omega loop, TEAD interating region 3 / : / 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 / WW domain / WW/rsp5/WWP domain signature. / WW domain superfamily / WW/rsp5/WWP domain profile. / Domain with 2 conserved Trp (W) residues / WW domain
Similarity search - Domain/homology
: / Transcriptional enhancer factor TEF-1 / Transcriptional coactivator YAP1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.214 Å
AuthorsMusil, D. / Freire, F.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2024
Title: Discovery of reversible and covalent TEAD 1 selective inhibitors MSC-1254 and MSC-5046 based on one scaffold.
Authors: Carswell, E. / Heinrich, T. / Petersson, C. / Gunera, J. / Garg, S. / Schwarz, D. / Schlesiger, S. / Fischer, F. / Eichhorn, T. / Calder, M. / Smith, G. / MacDonald, E. / Wilson, H. / Hazel, ...Authors: Carswell, E. / Heinrich, T. / Petersson, C. / Gunera, J. / Garg, S. / Schwarz, D. / Schlesiger, S. / Fischer, F. / Eichhorn, T. / Calder, M. / Smith, G. / MacDonald, E. / Wilson, H. / Hazel, K. / Trivier, E. / Broome, R. / Balsiger, A. / Sirohi, S. / Musil, D. / Freire, F. / Schilke, H. / Dillon, C. / Wienke, D.
History
DepositionJul 4, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 16, 2024Provider: repository / Type: Initial release
Revision 1.1Nov 6, 2024Group: Database references / Category: citation / Item: _citation.journal_volume

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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 coactivator YAP1
C: Transcriptional enhancer factor TEF-1
D: Transcriptional coactivator YAP1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,1218
Polymers64,3634
Non-polymers7584
Water82946
1
A: Transcriptional enhancer factor TEF-1
B: Transcriptional coactivator YAP1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,5604
Polymers32,1822
Non-polymers3792
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3380 Å2
ΔGint-31 kcal/mol
Surface area13310 Å2
2
C: Transcriptional enhancer factor TEF-1
D: Transcriptional coactivator YAP1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,5604
Polymers32,1822
Non-polymers3792
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3510 Å2
ΔGint-30 kcal/mol
Surface area12970 Å2
Unit cell
Length a, b, c (Å)43.992, 106.498, 166.162
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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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: Protein Transcriptional coactivator YAP1 / Yes-associated protein 1 / Protein yorkie homolog / Yes-associated protein YAP65 homolog


Mass: 6720.625 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: YAP1, YAP65 / Production host: Escherichia coli (E. coli) / References: UniProt: P46937
#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#4: Chemical ChemComp-A1IHH / ~{N}-[(4-phenoxyphenyl)methyl]imidazo[1,2-a]pyridine-3-carboxamide


Mass: 343.379 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H17N3O2 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 46 / 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: 3.02 Å3/Da / Density % sol: 59.32 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 4.6 / Details: 2M Sodium Formate, 0.1M Sodium Acetate pH 4.6

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.99998 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Mar 2, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99998 Å / Relative weight: 1
ReflectionResolution: 2.214→50.71 Å / Num. obs: 19089 / % possible obs: 90.2 % / Redundancy: 6.2 % / CC1/2: 1 / Rpim(I) all: 0.024 / Rrim(I) all: 0.066 / Net I/σ(I): 16.7
Reflection shellResolution: 2.214→2.551 Å / Num. unique obs: 954 / CC1/2: 0.789 / Rpim(I) all: 0.338

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Processing

Software
NameVersionClassification
BUSTER2.11.8 (23-JAN-2024)refinement
XDSdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.214→50.71 Å / Cor.coef. Fo:Fc: 0.924 / Cor.coef. Fo:Fc free: 0.9 / SU R Cruickshank DPI: 0.872 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.87 / SU Rfree Blow DPI: 0.343 / SU Rfree Cruickshank DPI: 0.348
RfactorNum. reflection% reflectionSelection details
Rfree0.2622 947 4.96 %RANDOM
Rwork0.2217 ---
obs0.2237 19089 47.9 %-
Displacement parametersBiso mean: 64.95 Å2
Baniso -1Baniso -2Baniso -3
1--0.1076 Å20 Å20 Å2
2--10.9527 Å20 Å2
3----10.8451 Å2
Refine analyzeLuzzati coordinate error obs: 0.38 Å
Refinement stepCycle: 1 / Resolution: 2.214→50.71 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4031 0 54 46 4131
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0084281HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.925770HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1498SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes772HARMONIC5
X-RAY DIFFRACTIONt_it4281HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.9
X-RAY DIFFRACTIONt_other_torsion18.77
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion531SEMIHARMONIC5
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_contact3063SEMIHARMONIC4
LS refinement shellResolution: 2.214→2.42 Å
RfactorNum. reflection% reflection
Rfree0.2876 -5.16 %
Rwork0.3065 386 -
obs--4.5 %
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)
11.9926-1.30150.74862.07431.09384.6083-0.1645-0.3475-0.06660.19160.31130.0603-0.0742-0.6786-0.1468-0.127-0.12130.03520.18640.0125-0.1418-11.2122-9.887323.3594
25.6451-1.42031.86653.64392.1586.9457-0.4517-0.82740.39470.49010.196-0.1412-1.0719-0.84220.25560.02870.24290.11730.0951-0.0487-0.3856-13.61.39432.6306
31.76750.40480.07111.06950.27273.91750.06160.05530.2685-0.1293-0.10280.09260.3286-0.28120.0412-0.03190.2863-0.10720.1389-0.1326-0.1454-8.99269.261264.5235
45.1071-1.0478-3.62144.14441.12466.794-0.03380.8535-0.4561-0.461-0.0440.38921.0225-0.67550.07770.14370.0607-0.2731-0.033-0.0892-0.3657-14.2319-1.275255.0567
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* }
2X-RAY DIFFRACTION2{ B|* }
3X-RAY DIFFRACTION3{ C|* }
4X-RAY DIFFRACTION4{ D|* }

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