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- PDB-6dl2: BRD4 bromodomain 1 in complex with HYB157 -

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Basic information

Entry
Database: PDB / ID: 6dl2
TitleBRD4 bromodomain 1 in complex with HYB157
ComponentsBromodomain-containing protein 4BRD4
KeywordsTRANSCRIPTION / Bromodomain
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 / 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-like / Histone Acetyltransferase; Chain A ...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-like / Histone Acetyltransferase; Chain A / Bromodomain, conserved site / Bromodomain signature. / Bromodomain / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-GUJ / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.47 Å
AuthorsMeagher, J.L. / Stuckey, J.A.
CitationJournal: J. Med. Chem. / Year: 2018
Title: Discovery of QCA570 as an Exceptionally Potent and Efficacious Proteolysis Targeting Chimera (PROTAC) Degrader of the Bromodomain and Extra-Terminal (BET) Proteins Capable of Inducing Complete ...Title: Discovery of QCA570 as an Exceptionally Potent and Efficacious Proteolysis Targeting Chimera (PROTAC) Degrader of the Bromodomain and Extra-Terminal (BET) Proteins Capable of Inducing Complete and Durable Tumor Regression.
Authors: Qin, C. / Hu, Y. / Zhou, B. / Fernandez-Salas, E. / Yang, C.Y. / Liu, L. / McEachern, D. / Przybranowski, S. / Wang, M. / Stuckey, J. / Meagher, J. / Bai, L. / Chen, Z. / Lin, M. / Yang, J. ...Authors: Qin, C. / Hu, Y. / Zhou, B. / Fernandez-Salas, E. / Yang, C.Y. / Liu, L. / McEachern, D. / Przybranowski, S. / Wang, M. / Stuckey, J. / Meagher, J. / Bai, L. / Chen, Z. / Lin, M. / Yang, J. / Ziazadeh, D.N. / Xu, F. / Hu, J. / Xiang, W. / Huang, L. / Li, S. / Wen, B. / Sun, D. / Wang, S.
History
DepositionMay 31, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 17, 2019Provider: repository / Type: Initial release
Revision 1.1Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,5273
Polymers15,1531
Non-polymers3732
Water2,648147
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)37.512, 43.130, 79.306
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Bromodomain-containing protein 4 / BRD4 / Protein HUNK1


Mass: 15153.364 Da / Num. of mol.: 1
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-GUJ / 3-benzyl-2,9-dimethyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine


Mass: 311.401 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H17N3OS
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 147 / Source method: isolated from a natural source / Formula: H2O

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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: 2.12 Å3/Da / Density % sol: 41.89 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 16% Peg 3350, 0.2 M Potassium Chloride

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.9787 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Apr 24, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9787 Å / Relative weight: 1
ReflectionResolution: 1.47→50 Å / Num. obs: 22421 / % possible obs: 98.9 % / Redundancy: 6.9 % / Biso Wilson estimate: 19.89 Å2 / Rmerge(I) obs: 0.05 / Rpim(I) all: 0.021 / Rrim(I) all: 0.054 / Χ2: 1.227 / Net I/σ(I): 13.5
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.47-1.56.80.19111110.9810.0780.2070.90799.6
1.5-1.527.10.17411060.9850.070.1870.914100
1.52-1.557.10.15511230.9890.0630.1680.927100
1.55-1.587.10.14411040.9890.0580.1551.059100
1.58-1.627.10.12611100.9920.0510.1361.046100
1.62-1.667.10.11311220.9930.0460.1221.131100
1.66-1.77.10.10810980.9940.0440.1171.153100
1.7-1.747.10.09611140.9940.0390.1041.178100
1.74-1.797.10.08611360.9950.0350.0931.24499.9
1.79-1.8570.0811120.9950.0330.0861.325100
1.85-1.9270.07211290.9940.0290.0771.322100
1.92-270.06811190.9960.0280.0731.354100
2-2.0970.05911380.9970.0240.0641.353100
2.09-2.270.05811270.9970.0240.0631.40199.7
2.2-2.336.90.05811240.9970.0230.0621.467100
2.33-2.516.80.0611480.9950.0250.0651.643100
2.51-2.776.60.05511330.9970.0230.0591.64399.8
2.77-3.176.60.05311650.9970.0220.0571.699.7
3.17-3.996.50.03711480.9980.0160.0411.08598
3.99-505.60.02810540.9990.0130.0310.6582.9

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
HKL-2000data reduction
HKL-2000data scaling
MOLREPphasing
BUSTER2.10.3refinement
PDB_EXTRACT3.24data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4LYI

4lyi


Resolution: 1.47→33.91 Å / Cor.coef. Fo:Fc: 0.937 / Cor.coef. Fo:Fc free: 0.933 / SU R Cruickshank DPI: 0.077 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.083 / SU Rfree Blow DPI: 0.079 / SU Rfree Cruickshank DPI: 0.074
RfactorNum. reflection% reflectionSelection details
Rfree0.216 1099 4.91 %RANDOM
Rwork0.197 ---
obs0.198 22368 98.5 %-
Displacement parametersBiso max: 103.81 Å2 / Biso mean: 25.26 Å2 / Biso min: 12.47 Å2
Baniso -1Baniso -2Baniso -3
1--5.4673 Å20 Å20 Å2
2--3.0295 Å20 Å2
3---2.4378 Å2
Refine analyzeLuzzati coordinate error obs: 0.19 Å
Refinement stepCycle: final / Resolution: 1.47→33.91 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1037 0 26 147 1210
Biso mean--21.21 33.15 -
Num. residues----128
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d375SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes203HARMONIC5
X-RAY DIFFRACTIONt_it1107HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion144SEMIHARMONIC5
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_contact1471SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d1107HARMONIC20.009
X-RAY DIFFRACTIONt_angle_deg1513HARMONIC20.91
X-RAY DIFFRACTIONt_omega_torsion3.22
X-RAY DIFFRACTIONt_other_torsion15.46
LS refinement shellResolution: 1.47→1.54 Å / Rfactor Rfree error: 0 / Total num. of bins used: 11
RfactorNum. reflection% reflection
Rfree0.2209 125 4.35 %
Rwork0.1827 2749 -
all0.1843 2874 -
obs--97 %
Refinement TLS params.Method: refined / Origin x: 11.5408 Å / Origin y: -3.0734 Å / Origin z: -9.06 Å
111213212223313233
T-0.0398 Å2-0.0057 Å20.0366 Å2--0.0508 Å20.0013 Å2---0.0131 Å2
L0.7633 °2-0.4799 °2-0.4105 °2-1.3874 °20.5992 °2--2.4936 °2
S-0.107 Å °-0.0073 Å °-0.0908 Å °0.0522 Å °-0.0491 Å °0.1525 Å °0.2083 Å °-0.0566 Å °0.156 Å °
Refinement TLS groupSelection details: { A|* }

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