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

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Basic information

Entry
Database: PDB / ID: 7rek
TitleCrystal structure of the first bromodomain (BD1) of human BRD4 in complex with dual BRD4-JAK2 inhibitor MA9-086
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 / P-TEFb complex binding / negative regulation of DNA damage checkpoint / histone H4 reader activity / host-mediated suppression of viral transcription / positive regulation of G2/M transition of mitotic cell cycle / positive regulation of T-helper 17 cell lineage commitment / : / RNA polymerase II CTD heptapeptide repeat kinase activity / condensed nuclear chromosome ...RNA polymerase II C-terminal domain binding / P-TEFb complex binding / negative regulation of DNA damage checkpoint / histone H4 reader activity / host-mediated suppression of viral transcription / positive regulation of G2/M transition of mitotic cell cycle / positive regulation of T-helper 17 cell lineage commitment / : / RNA polymerase II CTD heptapeptide repeat kinase activity / condensed nuclear chromosome / transcription coregulator activity / positive regulation of transcription elongation by RNA polymerase II / p53 binding / chromosome / regulation of inflammatory response / histone binding / Potential therapeutics for SARS / transcription coactivator activity / positive regulation of canonical NF-kappaB signal transduction / transcription cis-regulatory region binding / chromatin remodeling / protein serine/threonine kinase activity / DNA damage response / chromatin binding / regulation of transcription by RNA polymerase II / chromatin / 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 / Brdt, bromodomain, repeat I / Brdt, bromodomain, repeat II / NET domain superfamily / NET domain profile. / : / NET domain / Bromodomain extra-terminal - transcription regulation / Bromodomain, conserved site ...Bromodomain protein 4, C-terminal / C-terminal domain of bromodomain protein 4 / Brdt, bromodomain, repeat I / Brdt, bromodomain, repeat II / NET domain superfamily / NET domain profile. / : / NET domain / Bromodomain extra-terminal - transcription regulation / Bromodomain, conserved site / Bromodomain signature. / Bromodomain / bromo domain / Bromodomain / Bromodomain (BrD) profile. / Bromodomain-like superfamily
Similarity search - Domain/homology
Chem-R6S / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.2 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 MA9-086
Authors: Karim, M.R. / Schonbrunn, E.
History
DepositionJul 13, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 21, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 18, 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 / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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: Bromodomain-containing protein 4
B: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,50210
Polymers30,0252
Non-polymers1,4788
Water5,044280
1
A: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,7515
Polymers15,0121
Non-polymers7394
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,7515
Polymers15,0121
Non-polymers7394
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)30.300, 40.280, 57.300
Angle α, β, γ (deg.)100.110, 104.400, 90.130
Int Tables number1
Space group name H-MP1
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11chain A
21(chain B and resid 43 through 167)

NCS domain segments:

Component-ID: 1 / Ens-ID: 1 / Beg auth comp-ID: MET / Beg label comp-ID: MET / End auth comp-ID: GLU / End label comp-ID: GLU / Auth seq-ID: 43 - 167 / Label seq-ID: 1 - 125

Dom-IDSelection detailsAuth asym-IDLabel asym-ID
1chain AAA
2(chain B and resid 43 through 167)BB

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Components

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


Mass: 15012.301 Da / Num. of mol.: 2 / Fragment: Bromo 1 domain residues 44-168
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-R6S / N~4~-[1-(tert-butylsulfonyl)-2,3-dihydro-1H-indol-6-yl]-N~2~-[3-fluoro-4-(1-methylpiperidin-4-yl)phenyl]-5-methylpyrimidine-2,4-diamine


Mass: 552.706 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H37FN6O2S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 280 / 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: 2.22 Å3/Da / Density % sol: 44.56 %
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: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Mar 16, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.2→39.61 Å / Num. obs: 72084 / % possible obs: 89.2 % / Redundancy: 1.842 % / Biso Wilson estimate: 12.69 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.03 / Rrim(I) all: 0.043 / Χ2: 1.054 / Net I/σ(I): 10.81 / Num. measured all: 132799 / Scaling rejects: 326
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
1.2-1.231.8240.2172.776303598134550.9430.30757.8
1.23-1.261.8510.1953.078966585148450.9510.27682.8
1.26-1.31.9010.1653.749617565650600.9660.23389.5
1.3-1.341.8950.1444.469303546349090.970.20389.9
1.34-1.391.8530.1254.848946534248270.9770.17790.4
1.39-1.431.8130.1035.648590521447370.9840.14590.9
1.43-1.491.7010.086.717616495244780.9890.11390.4
1.49-1.551.8760.0698.418318479044340.990.09892.6
1.55-1.621.9110.0579.778063459642200.9930.08191.8
1.62-1.71.8720.0511.187651440040880.9940.07192.9
1.7-1.791.8370.04512.897190417139150.9940.06393.9
1.79-1.91.7980.03914.756572392436550.9950.05593.1
1.9-2.031.6780.03316.45828373634730.9960.04793
2.03-2.191.8980.03119.536205344332690.9960.04394.9
2.19-2.41.9170.0321.135809317930310.9950.04295.3
2.4-2.681.8950.0321.845191286527400.9950.04395.6
2.68-3.11.8430.02722.64453253824160.9960.03895.2
3.1-3.791.6680.02622.213444214920650.9950.03696.1
3.79-5.371.9120.02224.453032163715860.9970.03196.9
5.37-39.611.9320.01924.5617029128810.9980.02796.6

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Processing

Software
NameVersionClassification
PHENIX1.19_4085refinement
XSCALEdata scaling
PDB_EXTRACT3.27data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7K6H

7k6h


Resolution: 1.2→39.61 Å / SU ML: 0.12 / Cross valid method: THROUGHOUT / σ(F): 1.99 / Phase error: 24.72 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1906 1298 1.8 %
Rwork0.1658 70784 -
obs0.1663 72082 89.27 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 71.33 Å2 / Biso mean: 20.0891 Å2 / Biso min: 10.56 Å2
Refinement stepCycle: final / Resolution: 1.2→39.61 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2095 0 102 280 2477
Biso mean--20.81 28.29 -
Num. residues----251
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A750X-RAY DIFFRACTION0.831TORSIONAL
12B750X-RAY DIFFRACTION0.831TORSIONAL
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.2-1.250.271060.2595758586465
1.25-1.30.24541410.22967739788088
1.3-1.370.23831460.19347940808690
1.37-1.460.20461470.18448011815891
1.46-1.570.19161480.16788084823292
1.57-1.730.18521500.15828208835893
1.73-1.980.21121510.168213836493
1.98-2.50.1691530.16128370852395
2.5-39.610.18341560.15698461861796
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)
16.12740.6162-0.9496.1523-1.68169.2916-0.0802-0.0166-0.36050.09270.1953-0.19330.555-0.02590.11860.20450.02020.0040.1041-0.0170.1967-5.4775-15.9117-18.0608
21.03422.0072-1.58473.8804-3.06342.4014-0.04390.001-0.2046-0.6782-0.3672-0.30920.36570.36880.42010.26560.05940.03820.25920.03140.21226.1418-0.8118-28.0566
35.74530.8202-0.90097.50921.3072.03820.00510.05280.2269-0.0271-0.0455-0.3297-0.54310.49490.09560.1955-0.0222-0.00830.19380.02220.14566.08929.8709-17.8677
41.29680.26810.39121.2220.82872.31220.0348-0.0847-0.11430.1262-0.0275-0.00360.19680.0170.03650.13390.01860.00410.13230.01310.1289-4.3725-4.6662-7.2993
50.3232-0.0134-0.30031.0334-0.23981.5318-0.01340.03360.0034-0.0582-0.0779-0.01640.06940.07590.11020.12290.01590.00360.1196-0.00650.1357-2.4581-3.6515-19.8366
64.63242.4346-2.32441.7393-0.9181.9348-0.03130.090.0918-0.02750.01430.0175-0.0333-0.0144-0.01250.13420.018-0.0070.1255-0.00050.1385-9.23571.5034-17.1855
73.47672.0683-1.73242.7878-1.31762.6190.08150.0260.23260.1007-0.03360.1265-0.2356-0.0886-0.05620.12110.0254-0.01320.1206-0.01450.1303-8.86857.6053-9.9463
85.9663-4.2952-2.6359.26752.54233.9823-0.33350.03-0.04970.86230.09910.25270.5213-0.21720.27610.1795-0.03060.00570.12320.02250.1337-2.55738.9185-33.0388
91.3936-0.414-1.24030.86711.99634.61850.045-0.00210.03070.1062-0.19020.08140.0024-0.4410.11120.1484-0.01220.00280.1543-0.02740.162-9.372726.0697-36.1199
101.3158-0.06630.00371.4646-0.43912.2341-0.0193-0.0164-0.1239-0.0287-0.0137-0.0010.21330.01780.03610.1408-0.00440.0110.13230.00120.15085.274311.18-44.0823
110.88-0.7122-0.0573.59153.61255.80.05860.03970.05030.1796-0.21260.19280.2086-0.33880.1170.1351-0.01570.01220.1518-0.00580.1513-7.250220.2465-33.3537
124.7256-2.6818-2.2441.92561.09951.7077-0.02-0.13460.12960.01260.04820.0031-0.0390.0156-0.04660.1398-0.01690.00220.1282-0.00740.14865.561921.6907-37.5658
131.2947-0.3008-0.87620.64710.38372.26110.14860.04210.1848-0.0606-0.0903-0.0144-0.2632-0.0623-0.12830.1563-0.0198-0.00050.1305-0.00220.1724.627128.1283-44.1059
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 43 through 47 )A43 - 47
2X-RAY DIFFRACTION2chain 'A' and (resid 48 through 60 )A48 - 60
3X-RAY DIFFRACTION3chain 'A' and (resid 61 through 68 )A61 - 68
4X-RAY DIFFRACTION4chain 'A' and (resid 69 through 96 )A69 - 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 167 )A140 - 167
8X-RAY DIFFRACTION8chain 'B' and (resid 43 through 52 )B43 - 52
9X-RAY DIFFRACTION9chain 'B' and (resid 53 through 76 )B53 - 76
10X-RAY DIFFRACTION10chain 'B' and (resid 77 through 106 )B77 - 106
11X-RAY DIFFRACTION11chain 'B' and (resid 107 through 121 )B107 - 121
12X-RAY DIFFRACTION12chain 'B' and (resid 122 through 139 )B122 - 139
13X-RAY DIFFRACTION13chain 'B' and (resid 140 through 168 )B140 - 168

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