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- PDB-8ead: Crystal structure of the first bromodomain (BD1) of human BRD4 in... -

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Basic information

Entry
Database: PDB / ID: 8ead
TitleCrystal structure of the first bromodomain (BD1) of human BRD4 in complex with dual BRD4-JAK2 inhibitor MA9-177
ComponentsBromodomain-containing protein 4
KeywordsGENE REGULATION / BET / JAK2 / dual BRD-kinase inhibitor
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-UY0 / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.65 Å
AuthorsKarim, M.R. / Schonbrunn, E.
Funding support United States, 1items
OrganizationGrant numberCountry
Leukemia & Lymphoma Society United States
CitationJournal: To Be Published
Title: Crystal structure of the first bromodomain (BD1) of human BRD4 in complex with dual BRD4-JAK2 inhibitor MA9-177
Authors: Karim, M.R. / Schonbrunn, E.
History
DepositionAug 29, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 7, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,7834
Polymers15,0991
Non-polymers6833
Water3,081171
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)37.953, 44.416, 78.646
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 / Protein HUNK1


Mass: 15099.380 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-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#3: Chemical ChemComp-UY0 / N-{2-chloro-5-[(5-methyl-2-{4-[2-(pyrrolidin-1-yl)ethoxy]anilino}pyrimidin-4-yl)amino]phenyl}-2-methylpropane-2-sulfonamide


Mass: 559.123 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H35ClN6O3S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 171 / 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: 2.2 Å3/Da / Density % sol: 43.96 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop
Details: 0.2 M Ammonium sulphate, 0.15 M Sodium chloride, 0.1 M Tris (pH 8.5), 25 % w/v PEG 3,350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.5418 Å
DetectorType: RIGAKU SATURN 944+ / Detector: CCD / Date: Jul 17, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.65→30 Å / Num. obs: 16124 / % possible obs: 96.7 % / Redundancy: 3.7 % / Biso Wilson estimate: 15.59 Å2 / Rmerge(I) obs: 0.067 / Rpim(I) all: 0.035 / Rrim(I) all: 0.076 / Χ2: 5.623 / Net I/σ(I): 26.7 / Num. measured all: 59382
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.65-1.682.40.1637070.9350.1230.2061.05688.3
1.68-1.712.40.1447170.9530.1080.1811.2787.2
1.71-1.742.40.1387300.9530.1020.1721.3191
1.74-1.782.40.1287540.9680.0950.161.46290.4
1.78-1.822.50.1157660.9740.0850.1431.42494.3
1.82-1.862.50.1087730.9730.080.1351.97794
1.86-1.92.60.1167920.9740.0810.1423.97697.5
1.9-1.962.90.1347950.9580.0870.1616.21797.2
1.96-2.013.20.1358300.9620.080.1588.37598.9
2.01-2.083.40.1238050.9620.0730.1448.93398.8
2.08-2.153.50.1198110.9730.0680.1389.5199
2.15-2.243.70.1168330.980.0640.1339.66999
2.24-2.343.90.1158180.9770.0620.1319.08299.3
2.34-2.464.40.1098200.9750.0570.1238.06799.5
2.46-2.625.10.1048300.9830.0510.1166.97799.5
2.62-2.825.20.0868410.9850.0430.0975.60499.8
2.82-3.15.20.0688370.9930.0330.0764.79599.8
3.1-3.555.10.0538560.9940.0260.0593.83499.7
3.55-4.4750.0458670.9930.0220.054.20199.9
4.47-304.70.0459420.9940.0230.0513.931100

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Processing

Software
NameVersionClassification
HKL-2000data scaling
PHENIX1.19_4085refinement
PDB_EXTRACT3.27data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7REL

7rel


Resolution: 1.65→29.44 Å / SU ML: 0.12 / Cross valid method: THROUGHOUT / σ(F): 1.37 / Phase error: 18.37 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1948 804 5 %
Rwork0.151 15280 -
obs0.1532 16084 96.65 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 86.6 Å2 / Biso mean: 21.5079 Å2 / Biso min: 7.73 Å2
Refinement stepCycle: final / Resolution: 1.65→29.44 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1060 0 87 171 1318
Biso mean--24.28 27.21 -
Num. residues----127
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 (%)
1.65-1.750.21441200.15112281240188
1.75-1.890.21721280.16042434256294
1.89-2.080.19751340.15242557269198
2.08-2.380.20611380.14572602274099
2.38-2.990.17481380.151626202758100
2.99-29.440.19251460.150527862932100
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)
14.7463-0.0346-0.41042.7689-0.05522.22280.2066-0.1279-0.44710.0511-0.0803-0.16290.45280.1804-0.01720.21390.054-0.03510.11320.04770.115614.8603-9.920214.4841
20.4314-0.24430.94212.9686-3.04715.2908-0.02860.0464-0.01030.5351-0.1282-0.0101-0.62880.07210.10330.219-0.0017-0.00060.1235-0.00490.13869.747411.418420.7621
32.46311.9622.85959.50732.04843.5232-0.0954-0.1511-0.00850.13-0.07810.1025-0.218-0.33430.18480.1050.03730.00590.13210.0070.10384.15648.72087.1017
42.2738-1.65460.04223.69460.79812.0025-0.05080.1503-0.21480.1010.00780.22230.22170.09480.05010.07170.00120.00850.0872-0.00650.07959.301-5.52941.6204
51.51930.08710.3393.08371.20653.8321-0.0646-0.02850.0240.2851-0.0125-0.00610.16460.08130.08350.10580.0035-0.010.0840.01910.042913.81150.705713.678
61.9027-1.4202-1.61713.88192.65095.175-0.0267-0.03070.05370.06470.0782-0.2336-0.18640.2724-0.08540.0819-0.0206-0.01970.09250.01250.109217.93014.71776.7583
78.18432.2677-1.95523.9597-3.47363.04750.05920.9347-0.0479-0.55090.0519-0.326-0.06850.9716-0.07070.1886-0.01750.04930.2786-0.01290.111818.9154-2.4399-8.1968
81.35690.26990.37216.66692.79063.6708-0.1190.03370.1259-0.38370.17080.0974-0.32160.0403-0.03320.0966-0.0107-0.00560.08140.0150.09911.977110.2818-0.4508
98.32352.70233.51491.22650.97291.5658-0.1451-1.3860.45431.27650.18970.2291-0.7418-0.19370.05050.70550.06840.01670.3011-0.05880.296711.364122.642916.8176
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 42 through 51 )A42 - 51
2X-RAY DIFFRACTION2chain 'A' and (resid 52 through 68 )A52 - 68
3X-RAY DIFFRACTION3chain 'A' and (resid 69 through 75 )A69 - 75
4X-RAY DIFFRACTION4chain 'A' and (resid 76 through 96 )A76 - 96
5X-RAY DIFFRACTION5chain 'A' and (resid 97 through 121 )A97 - 121
6X-RAY DIFFRACTION6chain 'A' and (resid 122 through 139 )A122 - 139
7X-RAY DIFFRACTION7chain 'A' and (resid 140 through 144 )A140 - 144
8X-RAY DIFFRACTION8chain 'A' and (resid 145 through 163 )A145 - 163
9X-RAY DIFFRACTION9chain 'A' and (resid 164 through 168 )A164 - 168

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