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- PDB-7l9m: Crystal structure of the first bromodomain (BD1) of human BRD4 in... -

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Basic information

Entry
Database: PDB / ID: 7l9m
TitleCrystal structure of the first bromodomain (BD1) of human BRD4 in complex with bivalent inhibitor GXH-II-083
ComponentsBromodomain-containing protein 4
KeywordsTRANSCRIPTION/TRANSCRIPTION INHIBITOR / BET / ERK5 / dual BRD-kinase inhibitor / GENE REGULATION / TRANSCRIPTION-TRANSCRIPTION INHIBITOR complex
Function / homology
Function and homology information


RNA polymerase II C-terminal domain binding / negative regulation of DNA damage checkpoint / P-TEFb complex binding / negative regulation by host of viral transcription / positive regulation of T-helper 17 cell lineage commitment / positive regulation of G2/M transition of mitotic cell cycle / histone reader activity / RNA polymerase II CTD heptapeptide repeat kinase activity / condensed nuclear chromosome / positive regulation of transcription elongation by RNA polymerase II ...RNA polymerase II C-terminal domain binding / negative regulation of DNA damage checkpoint / P-TEFb complex binding / negative regulation by host of viral transcription / positive regulation of T-helper 17 cell lineage commitment / positive regulation of G2/M transition of mitotic cell cycle / histone reader activity / RNA polymerase II CTD heptapeptide repeat kinase activity / condensed nuclear chromosome / positive regulation of transcription elongation by RNA polymerase II / transcription coregulator activity / lysine-acetylated histone binding / p53 binding / chromosome / regulation of inflammatory response / positive regulation of canonical NF-kappaB signal transduction / Potential therapeutics for SARS / transcription coactivator activity / transcription cis-regulatory region binding / chromatin remodeling / DNA damage response / chromatin binding / chromatin / regulation of transcription by RNA polymerase II / positive regulation of DNA-templated transcription / enzyme binding / positive regulation of transcription by RNA polymerase II / nucleoplasm / nucleus
Similarity search - Function
Bromodomain protein 4, C-terminal / C-terminal domain of bromodomain protein 4 / NET domain superfamily / NET domain profile. / Brdt, bromodomain, repeat II / Brdt, bromodomain, repeat I / NET domain / Bromodomain extra-terminal - transcription regulation / Bromodomain, conserved site / Bromodomain signature. ...Bromodomain protein 4, C-terminal / C-terminal domain of bromodomain protein 4 / NET domain superfamily / NET domain profile. / Brdt, bromodomain, repeat II / Brdt, bromodomain, repeat I / NET domain / Bromodomain extra-terminal - transcription regulation / Bromodomain, conserved site / Bromodomain signature. / Bromodomain / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily
Similarity search - Domain/homology
Chem-XR4 / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.45 Å
AuthorsKarim, M.R. / Schonbrunn, E.
CitationJournal: J.Med.Chem. / Year: 2022
Title: Bivalent BET Bromodomain Inhibitors Confer Increased Potency and Selectivity for BRDT via Protein Conformational Plasticity.
Authors: Guan, X. / Cheryala, N. / Karim, R.M. / Chan, A. / Berndt, N. / Qi, J. / Georg, G.I. / Schonbrunn, E.
History
DepositionJan 4, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 12, 2022Provider: repository / Type: Initial release
Revision 1.1Aug 3, 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 1.2Aug 24, 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: Bromodomain-containing protein 4
B: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,9307
Polymers30,1992
Non-polymers1,7315
Water5,765320
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)30.270, 40.070, 57.350
Angle α, β, γ (deg.)100.100, 104.610, 90.070
Int Tables number1
Space group name H-MP1
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11(chain A and (resid 42 through 60 or resid 62...
21(chain B and (resid 42 through 60 or resid 62...

NCS domain segments:
Dom-IDComponent-IDEns-IDSelection detailsAuth asym-IDAuth seq-ID
111(chain A and (resid 42 through 60 or resid 62...A42 - 60
121(chain A and (resid 42 through 60 or resid 62...A62 - 63
131(chain A and (resid 42 through 60 or resid 62...A65 - 67
141(chain A and (resid 42 through 60 or resid 62...A69 - 77
151(chain A and (resid 42 through 60 or resid 62...A42 - 168
161(chain A and (resid 42 through 60 or resid 62...A82 - 84
171(chain A and (resid 42 through 60 or resid 62...A42 - 168
181(chain A and (resid 42 through 60 or resid 62...A131 - 168
211(chain B and (resid 42 through 60 or resid 62...B42 - 60
221(chain B and (resid 42 through 60 or resid 62...B62 - 63
231(chain B and (resid 42 through 60 or resid 62...B65 - 67
241(chain B and (resid 42 through 60 or resid 62...B69 - 77
251(chain B and (resid 42 through 60 or resid 62...B42 - 168
261(chain B and (resid 42 through 60 or resid 62...B8
271(chain B and (resid 42 through 60 or resid 62...B131 - 168

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Components

#1: Protein Bromodomain-containing protein 4 / Protein HUNK1


Mass: 15099.380 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRD4, HUNK1 / Production host: Escherichia coli (E. coli) / References: UniProt: O60885
#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-XR4 / N,N'-[(1,19-dioxo-4,7,10,13,16-pentaoxanonadecane-1,19-diyl)di(piperidine-1,4-diyl)]bis(4-{[4-({3-[(tert-butylsulfonyl)amino]-4-chlorophenyl}amino)-5-methylpyrimidin-2-yl]amino}-2-fluorobenzamide)


Mass: 1482.545 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C68H88Cl2F2N14O13S2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 320 / 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: 2.19 Å3/Da / Density % sol: 43.88 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop
Details: 0.2 M Ammonium sulfate, 0.1 M Tris HCl pH 8.5, 25% PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 0.8266 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Feb 2, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.8266 Å / Relative weight: 1
ReflectionResolution: 1.45→29.08 Å / Num. obs: 40473 / % possible obs: 88.9 % / Redundancy: 2.563 % / Biso Wilson estimate: 24.334 Å2 / CC1/2: 0.947 / Rmerge(I) obs: 0.201 / Rrim(I) all: 0.236 / Χ2: 1.319 / Net I/σ(I): 17.47 / Num. measured all: 103746 / Scaling rejects: 102
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
1.45-1.491.9390.2253.445501337328370.9170.31884.1
1.49-1.531.9380.1754.595495331428350.9430.24885.5
1.53-1.571.9650.1495.465462317327800.9540.21187.6
1.57-1.621.9550.126.795315309827190.970.1787.8
1.62-1.671.9490.1017.765106303826200.9780.14386.2
1.67-1.731.9410.0839.354841288524940.9850.11786.4
1.73-1.81.9230.0711.274324281822490.9880.09879.8
1.8-1.872.0940.08813.414679267322350.9780.11683.6
1.87-1.962.530.14615.445807255422950.9640.17789.9
1.96-2.052.7350.16318.316168249322550.9560.19490.5
2.05-2.163.1330.19521.166846238521850.9470.22991.6
2.16-2.293.4130.22124.157192222421070.9210.25894.7
2.29-2.453.3860.21525.776521205619260.9260.25293.7
2.45-2.653.1810.226.535919197118610.930.23594.4
2.65-2.93.3880.21333.265672179516740.9160.24893.3
2.9-3.243.5670.21938.345347159214990.9060.25594.2
3.24-3.743.4640.240.94687145013530.9070.23393.3
3.74-4.593.4130.19842.763983121111670.9190.23196.4
4.59-6.483.5040.19941.4631439288970.9230.23296.7
6.48-29.083.5840.21648.1517385074850.9270.25195.7

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Processing

Software
NameVersionClassification
PHENIX1.18.2-3874_3874refinement
XSCALEdata scaling
PDB_EXTRACT3.25data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3MXF

3mxf


Resolution: 1.45→29.08 Å / SU ML: 0.08 / Cross valid method: THROUGHOUT / σ(F): 2.02 / Phase error: 20.95 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2018 1012 2.5 %
Rwork0.176 39457 -
obs0.1767 40469 88.94 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 57.22 Å2 / Biso mean: 21.0525 Å2 / Biso min: 9.63 Å2
Refinement stepCycle: final / Resolution: 1.45→29.08 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2092 0 117 320 2529
Biso mean--26.48 28.32 -
Num. residues----254
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.022292
X-RAY DIFFRACTIONf_angle_d2.3193119
X-RAY DIFFRACTIONf_dihedral_angle_d23.685319
X-RAY DIFFRACTIONf_chiral_restr0.281318
X-RAY DIFFRACTIONf_plane_restr0.015394
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A676X-RAY DIFFRACTION3.764TORSIONAL
12B676X-RAY DIFFRACTION3.764TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 7

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.45-1.530.20711380.20025392553085
1.53-1.620.2121420.17525529567188
1.62-1.750.21311400.17625471561186
1.75-1.920.22511360.1835301543784
1.92-2.20.22621490.18115796594591
2.2-2.770.22291520.19085958611094
2.77-29.080.17291550.16266010616595
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)
10.21020.1468-0.68554.1169-1.97952.9943-0.01340.1034-0.086-0.5031-0.2167-0.30910.32550.23180.18610.17080.06320.00160.16280.0110.14521.8234-1.2729-23.8399
21.0487-0.2861-0.40252.018-1.78253.7611-0.0308-0.21430.07040.1631-0.0486-0.0379-0.37380.35160.03220.171-0.014-0.02890.16460.01190.14643.967711.8139-12.135
31.441-0.0971-0.28750.75350.38561.79970.0017-0.00970.01320.057-0.04830.0268-0.0217-0.05790.04060.08510.0125-0.010.0843-0.00510.0942-7.34113.8163-12.2433
40.10140.28640.01322.47841.23541.67990.0245-0.1835-0.02940.5942-0.20160.24830.348-0.15660.11310.2188-0.06220.03460.1754-0.00430.1577-21.47918.748226.6822
50.6424-0.23030.14144.76761.89545.42020.0032-0.01410.28190.1091-0.10780.3448-0.2431-0.52510.22570.16210.02160.00110.1695-0.0330.1881-25.161124.060119.4815
61.051-0.7301-1.09794.50412.56063.1016-0.04120.15370.05380.0266-0.12680.3836-0.3422-0.26620.14820.14350.0013-0.00830.1483-0.01880.179-21.524918.91689.7811
71.757-0.11270.12182.1053-0.76511.8436-0.03120.068-0.1903-0.2495-0.0221-0.03840.31720.06540.08520.1687-0.0060.02540.13060.0030.1522-11.66035.19768.0726
81.33370.0565-0.64831.51790.22591.29350.0088-0.0271-0.04070.0688-0.11910.04310.0716-0.10650.11750.118-0.00730.00020.11480.01110.1178-16.443710.237521.0584
92.4956-1.1243-0.86151.18010.47611.2405-0.0598-0.1360.0410.06710.01390.0668-0.0541-0.01720.05820.1183-0.0098-0.00310.1074-0.00180.13-9.620415.468418.457
105.43211.84460.12264.89910.24444.68090.1013-0.014-0.0879-0.1388-0.0934-0.45710.14120.02470.0150.0881-0.02170.00360.1685-0.00960.13381.835711.71967.6914
112.9076-1.9636-1.42673.67582.28113.29550.1440.13080.3447-0.0477-0.04380.0092-0.28780.1136-0.07930.1559-0.02560.00210.110.02270.1759-10.342222.13719.7149
124.24490.531.80494.1691-2.12362.1125-0.0634-0.60440.15920.04680.29240.279-0.5553-0.1981-0.23470.28590.0333-0.01630.2579-0.01660.2306-21.610131.248124.3063
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 42 through 60 )A42 - 60
2X-RAY DIFFRACTION2chain 'A' and (resid 61 through 76 )A61 - 76
3X-RAY DIFFRACTION3chain 'A' and (resid 77 through 168 )A77 - 168
4X-RAY DIFFRACTION4chain 'B' and (resid 42 through 60 )B42 - 60
5X-RAY DIFFRACTION5chain 'B' and (resid 61 through 68 )B61 - 68
6X-RAY DIFFRACTION6chain 'B' and (resid 69 through 76 )B69 - 76
7X-RAY DIFFRACTION7chain 'B' and (resid 77 through 96 )B77 - 96
8X-RAY DIFFRACTION8chain 'B' and (resid 97 through 121 )B97 - 121
9X-RAY DIFFRACTION9chain 'B' and (resid 122 through 139 )B122 - 139
10X-RAY DIFFRACTION10chain 'B' and (resid 140 through 144 )B140 - 144
11X-RAY DIFFRACTION11chain 'B' and (resid 145 through 163 )B145 - 163
12X-RAY DIFFRACTION12chain 'B' and (resid 164 through 168 )B164 - 168

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