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- PDB-8fmu: Crystal structure of human Brachyury G177D variant in complex wit... -

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Basic information

Entry
Database: PDB / ID: 8fmu
TitleCrystal structure of human Brachyury G177D variant in complex with SJF-4601
ComponentsT-box transcription factor T
KeywordsTRANSCRIPTION / Brachyury / T-Box Transcription Factor / TBXT / TBXT C006 / SJF-4601
Function / homology
Function and homology information


primitive streak formation / anterior/posterior axis specification, embryo / Epithelial-Mesenchymal Transition (EMT) during gastrulation / cardiac muscle cell myoblast differentiation / Germ layer formation at gastrulation / Formation of definitive endoderm / Formation of axial mesoderm / Cardiogenesis / cell fate specification / Formation of paraxial mesoderm ...primitive streak formation / anterior/posterior axis specification, embryo / Epithelial-Mesenchymal Transition (EMT) during gastrulation / cardiac muscle cell myoblast differentiation / Germ layer formation at gastrulation / Formation of definitive endoderm / Formation of axial mesoderm / Cardiogenesis / cell fate specification / Formation of paraxial mesoderm / mesoderm development / mesoderm formation / somitogenesis / heart morphogenesis / negative regulation of DNA-binding transcription factor activity / sequence-specific double-stranded DNA binding / RNA polymerase II-specific DNA-binding transcription factor binding / 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 / negative regulation of transcription by RNA polymerase II / signal transduction / positive regulation of transcription by RNA polymerase II / nucleoplasm / nucleus
Similarity search - Function
Transcription factor, Brachyury / T-box transcription factor, DNA-binding domain / T-box transcription factor / Transcription factor, T-box, conserved site / T-box superfamily / T-box domain signature 2. / T-box domain signature 1. / T-box domain profile. / Domain first found in the mice T locus (Brachyury) protein / T-box / p53-like transcription factor, DNA-binding
Similarity search - Domain/homology
: / T-box transcription factor T
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.03 Å
AuthorsBebenek, A. / Linhares, B. / Jaime-Figueroa, S. / Butrin, A. / Crews, C.
Funding support United States, 1items
OrganizationGrant numberCountry
The Mark Foundation United States
CitationJournal: To Be Published
Title: Discovery and Development of the First Selective Brachyury Degrader
Authors: Chase, D. / Bebenek, A. / Nie, P. / Jaime-Figueroa, S. / Butrin, A. / Castro, D. / Linhares, B. / Crews, C.
History
DepositionDec 24, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 28, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: T-box transcription factor T
B: T-box transcription factor T
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,9774
Polymers44,1612
Non-polymers8162
Water5,242291
1
A: T-box transcription factor T
hetero molecules


  • defined by author&software
  • Evidence: gel filtration
  • 22.5 kDa, 1 polymers
Theoretical massNumber of molelcules
Total (without water)22,4882
Polymers22,0801
Non-polymers4081
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: T-box transcription factor T
hetero molecules


  • defined by author&software
  • 22.5 kDa, 1 polymers
Theoretical massNumber of molelcules
Total (without water)22,4882
Polymers22,0801
Non-polymers4081
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)58.892, 70.294, 81.874
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

#1: Protein T-box transcription factor T / Brachyury protein / Protein T


Mass: 22080.395 Da / Num. of mol.: 2 / Mutation: G177D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TBXT, T / Production host: Escherichia coli (E. coli) / References: UniProt: O15178
#2: Chemical ChemComp-Y3T / N-(3-chloro-4-fluorophenyl)-3-[4-(dimethylamino)butanamido]-4-methoxybenzamide


Mass: 407.866 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H23ClFN3O3
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 291 / 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: 1.92 Å3/Da / Density % sol: 35.9 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / Details: PEG3350 12%, 0.2 M NaSCN, 5 mM Betaine

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 1.1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Sep 17, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.1 Å / Relative weight: 1
ReflectionResolution: 2.03→45.14 Å / Num. obs: 22141 / % possible obs: 98.39 % / Redundancy: 6.1 % / Biso Wilson estimate: 31.2 Å2 / CC1/2: 0.977 / Net I/σ(I): 10.5
Reflection shellResolution: 2.03→2.1 Å / Num. unique obs: 2045 / CC1/2: 0.74

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.03→45.14 Å / SU ML: 0.27 / Cross valid method: FREE R-VALUE / σ(F): 1.38 / Phase error: 26 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2664 1119 5.06 %
Rwork0.1996 --
obs0.2028 22136 98.4 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.03→45.14 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2773 0 56 291 3120
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0032915
X-RAY DIFFRACTIONf_angle_d0.6413955
X-RAY DIFFRACTIONf_dihedral_angle_d7.326383
X-RAY DIFFRACTIONf_chiral_restr0.044413
X-RAY DIFFRACTIONf_plane_restr0.005508
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.03-2.130.32551300.23332464X-RAY DIFFRACTION94
2.13-2.240.28031390.22772633X-RAY DIFFRACTION100
2.24-2.380.31031320.22032618X-RAY DIFFRACTION100
2.38-2.560.31021470.22212649X-RAY DIFFRACTION100
2.56-2.820.29851520.22542631X-RAY DIFFRACTION100
2.82-3.230.32451470.2042645X-RAY DIFFRACTION100
3.23-4.060.22581480.17662657X-RAY DIFFRACTION99
4.07-45.140.21911240.18532720X-RAY DIFFRACTION95
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)
12.18160.68631.01221.0153-0.20652.07290.2924-0.2947-0.73170.2769-0.0868-0.220.4273-0.2171-0.19590.2469-0.03880.02170.22930.01650.306911.1643.349923.2328
22.68941.88650.82052.46250.62911.3949-0.07910.48450.02-0.09380.2678-0.00940.02930.2401-0.21940.21360.047-0.00710.25470.01410.254922.43659.390217.8419
31.41610.0910.45090.94590.31831.13520.01640.1228-0.0526-0.2616-0.04050.0742-0.1061-0.0191-0.00260.20010.0046-0.01010.208-0.01390.16556.44966.2285.7729
43.4883-1.30142.36562.0766-0.5363.7754-0.1657-0.60790.05180.23220.23520.3166-0.3349-0.1118-0.0720.39220.01480.04230.3578-0.00870.241514.126919.673434.0454
51.8050.67710.74631.2235-0.05151.8643-0.01520.0269-0.01670.0510.0787-0.1272-0.19840.0897-0.07390.15630.0220.02970.17310.01830.223515.714313.472412.1565
61.68220.02320.61121.6832-0.22572.67010.0548-0.0305-0.042-0.1508-0.03270.10950.0625-0.42780.00610.2266-0.01520.03110.18220.00270.22228.878111.839714.9917
74.0945-0.1-0.40946.03260.64375.3774-0.2131-0.1789-0.19410.3456-0.09080.10370.31480.09890.30.260.0444-0.03250.23610.01620.252523.34022.133729.3989
82.37651.1012-2.18442.2116-0.29893.99830.1409-0.31470.2878-0.04570.40490.3267-0.5616-0.6277-0.39810.39450.11530.00250.52110.13070.46727.171436.0661-16.3125
90.84240.18240.34411.44540.92123.1091-0.05230.02350.1319-0.15330.1073-0.0615-0.14430.0559-0.03660.2318-0.0077-0.00690.230.02220.267812.755227.2895-10.3116
104.11460.6393-2.90811.2442-0.8323.15170.24580.5993-0.2983-0.5873-0.12210.2833-0.4461-0.2187-0.10880.5833-0.046-0.00710.3702-0.01240.308710.67716.0957-29.4001
111.3802-0.2843-0.10780.7812-0.98261.40290.059-0.0088-0.0892-0.0125-0.03060.00750.0950.0559-0.02430.2081-0.0209-0.02340.2334-0.00220.20411.259525.1313-4.1729
122.2630.5483-0.04723.32961.70793.4394-0.09-0.0243-0.11110.23810.0405-0.17280.07740.52950.01710.32160.0119-0.00230.26210.01280.281719.233117.6506-12.7736
131.46540.53970.06132.2583-0.34482.0017-0.02750.0513-0.0886-0.1274-0.10850.1057-0.019-0.10780.10550.21270.0454-0.04360.2355-0.02890.257712.198825.5258-13.3907
142222221.7303-0.88111.10014.863-0.04087.0711-1.50772.1881-1.62151.2848-0.092-0.01460.82210.45530.840328.735938.1249-17.3508
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 41 through 63 )
2X-RAY DIFFRACTION2chain 'A' and (resid 64 through 76 )
3X-RAY DIFFRACTION3chain 'A' and (resid 77 through 96 )
4X-RAY DIFFRACTION4chain 'A' and (resid 97 through 111 )
5X-RAY DIFFRACTION5chain 'A' and (resid 112 through 165 )
6X-RAY DIFFRACTION6chain 'A' and (resid 166 through 200 )
7X-RAY DIFFRACTION7chain 'A' and (resid 201 through 213 )
8X-RAY DIFFRACTION8chain 'B' and (resid 41 through 55 )
9X-RAY DIFFRACTION9chain 'B' and (resid 56 through 96 )
10X-RAY DIFFRACTION10chain 'B' and (resid 97 through 112 )
11X-RAY DIFFRACTION11chain 'B' and (resid 113 through 142 )
12X-RAY DIFFRACTION12chain 'B' and (resid 143 through 165 )
13X-RAY DIFFRACTION13chain 'B' and (resid 166 through 214 )
14X-RAY DIFFRACTION14chain 'B' and (resid 215 through 215 )

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