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- PDB-7k0u: Crystal structure of the second bromodomain (BD2) of human TAF1 b... -

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Basic information

Entry
Database: PDB / ID: 7k0u
TitleCrystal structure of the second bromodomain (BD2) of human TAF1 bound to PLK1 kinase inhibitor BI2536
ComponentsTranscription initiation factor TFIID subunit 1
KeywordsGENE REGULATION / TAF1 / non-BET / BET / kinase inhibitor / PLK1 / dual BRD-kinase
Function / homology
Function and homology information


positive regulation of androgen receptor signaling pathway / negative regulation of protein autoubiquitination / RNA polymerase I general transcription initiation factor activity / regulation of cell cycle G1/S phase transition / histone H4K16ac reader activity / RNA polymerase II general transcription initiation factor binding / RNA polymerase II general transcription initiation factor activity / transcription factor TFIID complex / HIV Transcription Initiation / RNA Polymerase II HIV Promoter Escape ...positive regulation of androgen receptor signaling pathway / negative regulation of protein autoubiquitination / RNA polymerase I general transcription initiation factor activity / regulation of cell cycle G1/S phase transition / histone H4K16ac reader activity / RNA polymerase II general transcription initiation factor binding / RNA polymerase II general transcription initiation factor activity / transcription factor TFIID complex / 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 / midbrain development / cellular response to ATP / negative regulation of signal transduction by p53 class mediator / transcription initiation at RNA polymerase I promoter / ubiquitin conjugating enzyme activity / MLL1 complex / negative regulation of ubiquitin-dependent protein catabolic process / positive regulation of transcription initiation by RNA polymerase II / histone acetyltransferase activity / RNA polymerase II core promoter sequence-specific DNA binding / RNA polymerase II preinitiation complex assembly / histone acetyltransferase / transcription regulator inhibitor activity / 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 / mRNA transcription by RNA polymerase II / protein polyubiquitination / p53 binding / cellular response to UV / kinase activity / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / protein autophosphorylation / ubiquitin-dependent protein catabolic process / transcription regulator complex / Regulation of TP53 Activity through Phosphorylation / sequence-specific DNA binding / RNA polymerase II-specific DNA-binding transcription factor binding / transcription by RNA polymerase II / non-specific serine/threonine protein kinase / protein kinase activity / protein stabilization / protein heterodimerization activity / 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 / bromo domain / Bromodomain / Bromodomain (BrD) profile. / Bromodomain-like superfamily
Similarity search - Domain/homology
Chem-R78 / Transcription initiation factor TFIID subunit 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.52 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 6, 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 ...chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id ..._struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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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
B: Transcription initiation factor TFIID subunit 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,8526
Polymers31,7662
Non-polymers2,0874
Water181
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1080 Å2
ΔGint-1 kcal/mol
Surface area15620 Å2
Unit cell
Length a, b, c (Å)82.963, 82.963, 137.161
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11(chain A and (resid 1501 through 1590 or (resid 1591...
21(chain B and (resid 1501 through 1608 or (resid 1609...

NCS domain segments:

Ens-ID: 1

Dom-IDComponent-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11ASPASPTHRTHR(chain A and (resid 1501 through 1590 or (resid 1591...AA1501 - 15903 - 92
12LYSLYSLYSLYS(chain A and (resid 1501 through 1590 or (resid 1591...AA159193
13ASPASPGLUGLU(chain A and (resid 1501 through 1590 or (resid 1591...AA1501 - 16283 - 130
14ASPASPGLUGLU(chain A and (resid 1501 through 1590 or (resid 1591...AA1501 - 16283 - 130
15ASPASPGLUGLU(chain A and (resid 1501 through 1590 or (resid 1591...AA1501 - 16283 - 130
16ASPASPGLUGLU(chain A and (resid 1501 through 1590 or (resid 1591...AA1501 - 16283 - 130
21ASPASPASPASP(chain B and (resid 1501 through 1608 or (resid 1609...BB1501 - 16083 - 110
22GLUGLUGLUGLU(chain B and (resid 1501 through 1608 or (resid 1609...BB1609111
23ASPASPTHRTHR(chain B and (resid 1501 through 1608 or (resid 1609...BB1501 - 16203 - 122
24ASPASPTHRTHR(chain B and (resid 1501 through 1608 or (resid 1609...BB1501 - 16203 - 122
25ASPASPTHRTHR(chain B and (resid 1501 through 1608 or (resid 1609...BB1501 - 16203 - 122
26ASPASPTHRTHR(chain B and (resid 1501 through 1608 or (resid 1609...BB1501 - 16203 - 122

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Components

#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: 15882.812 Da / Num. of mol.: 2
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) / Strain (production host): BL21(DE3)
References: UniProt: P21675, histone acetyltransferase, non-specific serine/threonine protein kinase
#2: Chemical
ChemComp-R78 / 4-{[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl]amino}-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide


Mass: 521.654 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C28H39N7O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1 / 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: 3.73 Å3/Da / Density % sol: 66.98 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop
Details: 0.1 M HEPES (pH 7.5), 10% PEG 8,000, 8% Ethylene glycol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-BM / Wavelength: 1 Å
DetectorType: MARMOSAIC 325 mm CCD / Detector: CCD / Date: Oct 21, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.52→137.16 Å / Num. obs: 16873 / % possible obs: 99.9 % / Redundancy: 14.2 % / CC1/2: 0.999 / Rmerge(I) obs: 0.068 / Rpim(I) all: 0.019 / Rrim(I) all: 0.071 / Net I/σ(I): 20.1 / Num. measured all: 240026 / Scaling rejects: 314
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.52-2.6214.60.4872727318670.9850.1320.5044.2100
9.09-137.169.90.033416942210.0110.0353694.5

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
Aimless0.5.1data scaling
PDB_EXTRACT3.25data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3UV4

3uv4


Resolution: 2.52→53.94 Å / SU ML: 0.35 / Cross valid method: THROUGHOUT / σ(F): 1.51 / Phase error: 30.45 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2455 837 5 %
Rwork0.2096 15898 -
obs0.2114 16735 99.37 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 171.16 Å2 / Biso mean: 86.3377 Å2 / Biso min: 40.38 Å2
Refinement stepCycle: final / Resolution: 2.52→53.94 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1989 0 152 1 2142
Biso mean--79.67 95.01 -
Num. residues----248
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A730X-RAY DIFFRACTION2.734TORSIONAL
12B730X-RAY DIFFRACTION2.734TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 6

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.52-2.680.37121350.30282586272199
2.68-2.880.33331360.27492571270799
2.88-3.170.33931380.277926222760100
3.18-3.630.27251390.234926422781100
3.63-4.580.20291410.175126762817100
4.58-53.940.21391480.18792801294999
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)
17.10481.23672.10659.17665.70247.0768-0.26210.34170.2731-1.74130.4786-0.2972-0.92830.2151-0.10030.5427-0.0610.00390.40180.08590.6529-6.58529.158-31.108
28.5405-3.09244.23882.6498-0.48624.7244-0.4507-0.26710.79410.5808-0.0212-0.0778-0.2653-0.23640.49280.68210.0901-0.05140.5798-0.09160.6136-0.27234.274-10.745
39.48791.86451.11578.24472.72492.0190.8919-0.1916-0.62620.3713-0.02980.30840.2874-1.0998-1.0280.4758-0.00640.01180.63750.00950.68611.32423.368-7.103
42.4982-0.8512.20973.57710.2944.29260.1075-0.3565-0.07340.535-0.1606-0.08530.8446-0.33660.05330.4794-0.1055-0.05930.5425-0.02460.5842-5.55324.979-16.435
55.5042.20624.08651.48651.22833.2855-0.1996-1.00080.62670.1772-0.17070.3646-0.9731-1.51940.54920.48420.1776-0.00910.6692-0.11550.6758-14.68931.903-15.905
64.07051.11831.90184.39010.22853.42720.02460.48-0.6174-0.3770.0429-0.26840.77440.4754-0.11290.7765-0.00460.00010.67740.0430.647-10.57916.154-36.611
76.3766-1.5082-0.17439.4321-1.08622.0163-0.3855-0.4156-0.0706-0.03780.4004-0.6749-0.15651.0402-0.01880.93260.12240.03941.3457-0.08050.968110.15631.584-34.846
82.6040.09512.92762.79860.14043.29960.12270.3051-0.1964-0.70830.1340.07180.12770.8615-0.19331.06350.12640.11541.1660.00020.87983.929.491-51.619
91.17410.11122.66270.7367-0.60846.81160.19830.4527-0.0873-0.2244-0.0393-0.44020.26181.5211-0.09311.08260.17350.18841.7548-0.03911.176916.27730.394-47.094
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN A AND RESID 1501:1517 )A1501 - 1517
2X-RAY DIFFRACTION2( CHAIN A AND RESID 1518:1539 )A1518 - 1539
3X-RAY DIFFRACTION3( CHAIN A AND RESID 1540:1549 )A1540 - 1549
4X-RAY DIFFRACTION4( CHAIN A AND RESID 1550:1587 )A1550 - 1587
5X-RAY DIFFRACTION5( CHAIN A AND RESID 1588:1607 )A1588 - 1607
6X-RAY DIFFRACTION6( CHAIN A AND RESID 1608:1628 )A1608 - 1628
7X-RAY DIFFRACTION7( CHAIN B AND RESID 1501:1517 )B1501 - 1517
8X-RAY DIFFRACTION8( CHAIN B AND RESID 1518:1564 )B1518 - 1564
9X-RAY DIFFRACTION9( CHAIN B AND RESID 1565:1620 )B1565 - 1620

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