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- PDB-7k27: Crystal structure of the tandem bromodomain (BD1, BD2) of human T... -

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Basic information

Entry
Database: PDB / ID: 7k27
TitleCrystal structure of the tandem bromodomain (BD1, BD2) of human TAF1 bound to ATR inhibitor AZ20
ComponentsTranscription initiation factor TFIID subunit 1
KeywordsGENE REGULATION / Bromodomain / TAF1 / non-BET / BET / kinase inhibitor / ATR / dual BRD-kinase / transferase
Function / homology
Function and homology information


negative regulation of protein autoubiquitination / regulation of cell cycle G1/S phase transition / RNA polymerase I general transcription initiation factor activity / positive regulation of androgen receptor activity / transcription regulator inhibitor activity / RNA polymerase II general transcription initiation factor binding / midbrain development / cellular response to ATP / transcription factor TFIID complex / RNA polymerase II general transcription initiation factor activity ...negative regulation of protein autoubiquitination / regulation of cell cycle G1/S phase transition / RNA polymerase I general transcription initiation factor activity / positive regulation of androgen receptor activity / transcription regulator inhibitor activity / RNA polymerase II general transcription initiation factor binding / midbrain development / cellular response to ATP / transcription factor TFIID complex / RNA polymerase II general transcription initiation factor activity / HIV Transcription Initiation / RNA Polymerase II HIV Promoter Escape / Transcription of the HIV genome / RNA Polymerase II Promoter Escape / RNA Polymerase II Transcription Pre-Initiation And Promoter Opening / RNA Polymerase II Transcription Initiation / RNA Polymerase II Transcription Initiation And Promoter Clearance / ubiquitin conjugating enzyme activity / transcription initiation at RNA polymerase I promoter / MLL1 complex / positive regulation of transcription initiation by RNA polymerase II / RNA polymerase II core promoter sequence-specific DNA binding / negative regulation of ubiquitin-dependent protein catabolic process / histone acetyltransferase activity / RNA polymerase II preinitiation complex assembly / histone acetyltransferase / RNA Polymerase II Pre-transcription Events / TBP-class protein binding / regulation of signal transduction by p53 class mediator / nuclear receptor binding / transcription initiation at RNA polymerase II promoter / peptidyl-threonine phosphorylation / lysine-acetylated histone binding / mRNA transcription by RNA polymerase II / protein polyubiquitination / cellular response to UV / p53 binding / positive regulation of protein binding / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / kinase activity / ubiquitin-dependent protein catabolic process / peptidyl-serine phosphorylation / Regulation of TP53 Activity through Phosphorylation / RNA polymerase II-specific DNA-binding transcription factor binding / sequence-specific DNA binding / transcription regulator complex / transcription by RNA polymerase II / protein autophosphorylation / protein stabilization / non-specific serine/threonine protein kinase / protein kinase activity / protein heterodimerization activity / protein phosphorylation / negative regulation of gene expression / protein serine kinase activity / protein serine/threonine kinase activity / DNA damage response / chromatin / negative regulation of transcription by RNA polymerase II / positive regulation of transcription by RNA polymerase II / nucleoplasm / ATP binding / nucleus
Similarity search - Function
TAFII-230 TBP-binding / Transcription initiation factor TFIID subunit 1, animal / TAFII-230 TBP-binding domain superfamily / TATA box-binding protein binding / Zinc knuckle / Zinc knuckle / Transcription initiation factor TFIID subunit 1, histone acetyltransferase domain / Transcription initiation factor TFIID subunit 1 / Protein of unknown function (DUF3591) / Bromodomain, conserved site ...TAFII-230 TBP-binding / Transcription initiation factor TFIID subunit 1, animal / TAFII-230 TBP-binding domain superfamily / TATA box-binding protein binding / Zinc knuckle / Zinc knuckle / Transcription initiation factor TFIID subunit 1, histone acetyltransferase domain / Transcription initiation factor TFIID subunit 1 / Protein of unknown function (DUF3591) / Bromodomain, conserved site / Bromodomain signature. / Bromodomain / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily
Similarity search - Domain/homology
Chem-VCD / Transcription initiation factor TFIID subunit 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.5 Å
AuthorsKarim, M.R. / Schonbrunn, E.
CitationJournal: J.Med.Chem. / Year: 2022
Title: Discovery of Dual TAF1-ATR Inhibitors and Ligand-Induced Structural Changes of the TAF1 Tandem Bromodomain.
Authors: Karim, R.M. / Yang, L. / Chen, L. / Bikowitz, M.J. / Lu, J. / Grassie, D. / Shultz, Z.P. / Lopchuk, J.M. / Chen, J. / Schonbrunn, E.
History
DepositionSep 8, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 22, 2021Provider: repository / Type: Initial release
Revision 1.1Mar 9, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Mar 23, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Oct 18, 2023Group: 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

Downloads & links

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Assembly

Deposited unit
A: Transcription initiation factor TFIID subunit 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,7998
Polymers30,9681
Non-polymers8317
Water4,612256
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)45.260, 54.590, 123.420
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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

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Protein , 1 types, 1 molecules A

#1: Protein Transcription initiation factor TFIID subunit 1 / Cell cycle gene 1 protein / TBP-associated factor 250 kDa / p250 / Transcription initiation factor ...Cell cycle gene 1 protein / TBP-associated factor 250 kDa / p250 / Transcription initiation factor TFIID 250 kDa subunit / TAFII250


Mass: 30968.256 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TAF1, BA2R, CCG1, CCGS, TAF2A / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: P21675, histone acetyltransferase, non-specific serine/threonine protein kinase

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Non-polymers , 5 types, 263 molecules

#2: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6O2
#3: Chemical ChemComp-VCD / 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-(methylsulfonyl)cyclopropyl]pyrimidin-2-yl}-1H-indole


Mass: 412.505 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H24N4O3S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 256 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.46 Å3/Da / Density % sol: 50.03 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop
Details: 0.2 M Magnesium chloride hexahydrate, 0.1 M BIS-TRIS pH 5.5, 25% w/v Polyethylene glycol 3,350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Mar 14, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.5→34.84 Å / Num. obs: 49801 / % possible obs: 99.9 % / Redundancy: 6.529 % / Biso Wilson estimate: 28.298 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.044 / Rrim(I) all: 0.048 / Χ2: 1.048 / Net I/σ(I): 21.77 / Num. measured all: 325145 / Scaling rejects: 3
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsCC1/2Rrim(I) all% possible all
1.5-1.546.7310.6293.3324412363136270.8840.68199.9
1.54-1.586.630.5074.1423536355535500.9190.5599.9
1.58-1.636.4730.4085.0522307345634460.9530.44399.7
1.63-1.686.0870.3226.120373335133470.9680.35399.9
1.68-1.736.5120.2677.821221326232590.9780.2999.9
1.73-1.796.930.2199.9921553311431100.9870.23699.9
1.79-1.866.9220.17612.121106305030490.9910.19100
1.86-1.946.8450.13215.5920043293029280.9940.14399.9
1.94-2.026.7540.10119.7219148283628350.9960.109100
2.02-2.126.6420.07824.1717814268326820.9970.085100
2.12-2.246.360.06129.0116357257625720.9970.06699.8
2.24-2.375.8380.053214308245324510.9980.05599.9
2.37-2.546.6930.04636.9315360229522950.9980.05100
2.54-2.746.8240.04141.5514734215921590.9990.044100
2.74-36.670.03645.8913166197419740.9990.039100
3-3.356.450.03249.2811622180318020.9990.03599.9
3.35-3.876.140.02953.139885161316100.9990.03299.8
3.87-4.745.5010.02552.357531137913690.9990.02899.3
4.74-6.716.3660.02655.46926108810880.9990.028100
6.71-34.845.7760.02454.7237436526480.9990.02699.4

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Processing

Software
NameVersionClassification
PHENIX1.18.2-3874_3874refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ID 7K03

7k03


Resolution: 1.5→34.84 Å / SU ML: 0.12 / Cross valid method: THROUGHOUT / σ(F): 1.37 / Phase error: 17.14 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1753 1245 2.5 %
Rwork0.1597 48553 -
obs0.1601 49798 99.88 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 88.16 Å2 / Biso mean: 28.7846 Å2 / Biso min: 13.63 Å2
Refinement stepCycle: final / Resolution: 1.5→34.84 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2018 0 117 256 2391
Biso mean--32.46 34.59 -
Num. residues----247
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 9 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all
1.5-1.560.18681370.181753315468
1.56-1.630.21741350.174652735408
1.63-1.720.20681370.162453315468
1.72-1.820.17931380.15853745512
1.82-1.970.18291370.158453395476
1.97-2.160.17551380.147353785516
2.16-2.480.15621380.146353885526
2.48-3.120.16751400.162954575597
3.12-34.840.17641450.163756825827
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)
11.63770.4144-0.93031.2153-0.21852.68390.028-0.14350.08860.18-0.01620.01090.0337-0.0987-0.02620.1408-0.00470.00040.1173-0.00820.1304-128.1294-153.0421134.8811
21.66390.4292-1.03831.4221-0.23342.80340.0157-0.0545-0.19110.0672-0.0992-0.02950.0384-0.00010.08430.1301-0.0029-0.01720.1465-0.01150.1865-137.1418-175.4521127.8321
35.9194-2.3643-1.59632.21373.39296.6045-0.1667-0.2384-0.1590.3467-0.00460.03340.451-0.48070.18830.3778-0.06610.02160.30270.05990.1751-147.3952-177.2135147.6288
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 1380 through 1501 )A0
2X-RAY DIFFRACTION2chain 'A' and (resid 1502 through 1606 )A0
3X-RAY DIFFRACTION3chain 'A' and (resid 1607 through 1626 )A0

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