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- PDB-6mh1: CRYSTAL STRUCTURE OF THE FIRST BROMODOMAIN OF HUMAN BRD4 IN COMPL... -

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Basic information

Entry
Database: PDB / ID: 6mh1
TitleCRYSTAL STRUCTURE OF THE FIRST BROMODOMAIN OF HUMAN BRD4 IN COMPLEX WITH HU-10, A 1,4,5-Trisubstituted Imidazole Analogue
ComponentsBromodomain-containing protein 4BRD4
KeywordsTRANSCRIPTION/TRANSCRIPTION INHIBITOR / CAP / HUNK1 / MCAP / PROTEIN BINDING-INHIBITOR COMPLEX / INHIBITOR / TRANSCRIPTION-INHIBITOR COMPLEX / Inflammation / MAP-Kinase Inhibition / 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 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 ...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 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-JQP / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.6 Å
AuthorsZhu, J.-Y. / Schonbrunn, E.
Funding support United States, 2items
OrganizationGrant numberCountry
National Science Foundation (NSF, United States)CHE-1352019 United States
American Heart Association15SDG25710427 United States
CitationJournal: J.Med.Chem. / Year: 2018
Title: Molecular Basis for the N-Terminal Bromodomain-and-Extra-Terminal-Family Selectivity of a Dual Kinase-Bromodomain Inhibitor.
Authors: Divakaran, A. / Talluri, S.K. / Ayoub, A.M. / Mishra, N.K. / Cui, H. / Widen, J.C. / Berndt, N. / Zhu, J.Y. / Carlson, A.S. / Topczewski, J.J. / Schonbrunn, E.K. / Harki, D.A. / Pomerantz, W.C.K.
History
DepositionSep 17, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 7, 2019Provider: repository / Type: Initial release
Revision 1.1Nov 27, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.2Mar 13, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
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
B: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,2707
Polymers30,1992
Non-polymers1,0715
Water5,206289
1
A: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,6664
Polymers15,0991
Non-polymers5673
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,6043
Polymers15,0991
Non-polymers5052
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)41.830, 59.510, 111.420
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: 15099.380 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 / Plasmid: PNIC28-BSA4 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3)-R3 / References: UniProt: O60885
#2: Chemical ChemComp-JQP / N-(3,5-dimethylphenyl)-4-[4-(4-fluorophenyl)-1-(piperidin-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine


Mass: 442.531 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H27FN6 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 289 / 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: 2.3 Å3/Da / Density % sol: 46.43 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 12.5 MG/ML BRD4, 5MM HEPES PH 7.5, 50MM SODIUM CHLORIDE, 0.5MM DTT, 50MM TRIS PH8.5, 0.1M AMMONIUM, SULFATE, 12.5% PEG 3,350, 10% DMSO, 1 MM HU-10

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.54178 Å
DetectorType: RIGAKU SATURN 944+ / Detector: CCD / Date: Jun 27, 2016 / Details: mirrors
RadiationMonochromator: mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 1.6→29.755 Å / Num. obs: 36520 / % possible obs: 97.3 % / Redundancy: 4.643 % / Biso Wilson estimate: 14.68 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.033 / Rrim(I) all: 0.036 / Χ2: 1.022 / Net I/σ(I): 28.58 / Num. measured all: 169551 / Scaling rejects: 2
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
1.6-1.642.7190.1266.886164273522670.9610.15682.9
1.64-1.692.9810.1068.477220265624220.9760.12891.2
1.69-1.743.1720.09910.017872259624820.9810.11895.6
1.74-1.793.2650.08112.677969250524410.9880.09797.4
1.79-1.853.3580.07114.958086243724080.9910.08498.8
1.85-1.913.4220.06517.258168240623870.9920.07799.2
1.91-1.983.4870.05720.327916228122700.9940.06799.5
1.98-2.073.6720.04924.038006219621800.9960.05899.3
2.07-2.164.060.04328.598509210320960.9970.0599.7
2.16-2.264.7820.0433.999775204920440.9980.04599.8
2.26-2.395.7830.03939.1911184193619340.9980.04299.9
2.39-2.536.8270.03743.5212514183418330.9990.0499.9
2.53-2.76.9180.03545.9812037174117400.9990.03899.9
2.7-2.926.8850.03448.1811098161316120.9990.03699.9
2.92-3.26.8120.03350.2210246150515040.9990.03699.9
3.2-3.586.8440.0352.199232135113490.9990.03299.9
3.58-4.136.8440.02654.248356122312210.9990.02899.8
4.13-5.066.7480.02653.86998103810370.9990.02899.9
5.06-7.166.6790.02752.0755508318310.9990.029100
7.16-29.7555.7380.02748.5226514964620.9990.02993.1

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
XSCALEdata scaling
PHASERphasing
PHENIX1.9_1692refinement
PDB_EXTRACT3.24data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.6→29.755 Å / SU ML: 0.18 / Cross valid method: THROUGHOUT / σ(F): 1.46 / Phase error: 18.23
RfactorNum. reflection% reflectionSelection details
Rfree0.2016 1826 5 %Random selection
Rwork0.1592 ---
obs0.1613 36514 97.29 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 145.05 Å2 / Biso mean: 24.7349 Å2 / Biso min: 6.28 Å2
Refinement stepCycle: final / Resolution: 1.6→29.755 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2124 0 150 289 2563
Biso mean--21.92 29.02 -
Num. residues----254
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0112267
X-RAY DIFFRACTIONf_angle_d1.2593082
X-RAY DIFFRACTIONf_chiral_restr0.049318
X-RAY DIFFRACTIONf_plane_restr0.008394
X-RAY DIFFRACTIONf_dihedral_angle_d12.661873
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 13

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.6-1.64330.28371170.21152229234683
1.6433-1.69160.24971300.18662472260291
1.6916-1.74620.23681370.18752607274496
1.7462-1.80860.24011380.17482626276498
1.8086-1.8810.22921410.17562679282099
1.881-1.96660.2131430.173827072850100
1.9666-2.07030.21071420.17282702284499
2.0703-2.19990.20891440.163727252869100
2.1999-2.36970.19691430.158727262869100
2.3697-2.60810.19011450.160927522897100
2.6081-2.98520.21041450.158327652910100
2.9852-3.75980.18481470.144727942941100
3.7598-29.76010.17311540.13922904305899
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)
14.6042-0.66550.06091.321.02383.2272-0.07820.6176-0.0507-0.07260.015-0.13460.11160.16220.00090.1624-0.04870.02650.14830.01250.14168.354125.16284.4696
21.1793-0.2823-0.57881.95220.66382.9513-0.0017-0.06360.03480.01870.0659-0.1688-0.2110.171-0.0410.1382-0.03040.03320.1005-0.01440.12387.185134.834814.3025
35.7856-2.7028-3.1022.0291-0.09844.7874-0.19811.2227-1.2328-0.4042-0.37080.220.70370.10720.55370.29490.04810.11580.7261-0.22380.562526.602824.56946.3926
45.3177-5.6266-3.81167.96334.46353.0352-0.02880.4079-0.2551-0.1915-0.18030.5302-0.0329-0.48790.21950.1584-0.0136-0.00680.201-0.0260.2061-3.864359.38637.2594
54.0581-0.33261.12762.40871.90974.4744-0.06730.2784-0.2146-0.0384-0.0001-0.06910.5550.0945-0.17020.1719-0.03650.06360.14190.00570.133416.019750.50664.8076
62.621-1.9571-3.81241.51172.69835.9773-0.2688-0.397-0.23870.36230.3367-0.14130.38720.50870.01730.18510.02380.00460.15110.00890.153914.805556.038119.2855
74.89772.6198-0.05233.3637-0.36755.61570.0244-0.4086-0.18350.51330.0221-0.12550.1611-0.10150.00970.20690.0430.00140.11950.01260.08458.745462.567424.8047
85.8862-0.52870.42340.05440.08392.3128-0.1081-0.17810.13880.20560.14130.4616-0.0621-0.4510.00280.1029-0.0080.05420.1864-0.00030.2323-4.936465.617317.718
92.3454-1.6454-1.41994.35021.46691.9641-0.05160.0924-0.105-0.04220.03220.03860.06330.01910.00050.088-0.0195-0.00680.0979-0.00760.05977.77462.53538.9925
104.7245-1.8162-1.08413.34170.73863.2126-0.1344-0.36090.15640.17860.2087-0.3344-0.18230.34970.00960.1174-0.0258-0.0180.1191-0.01090.116814.377769.32419.731
111.1236-1.0818-1.12561.09161.31222.16930.14750.606-0.5971-0.2168-0.0827-0.3410.45330.6097-0.21420.29560.16750.14740.38030.0070.54327.601854.4646.3262
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 42 through 68 )A42 - 68
2X-RAY DIFFRACTION2chain 'A' and (resid 69 through 163 )A69 - 163
3X-RAY DIFFRACTION3chain 'A' and (resid 164 through 168 )A164 - 168
4X-RAY DIFFRACTION4chain 'B' and (resid 42 through 51 )B42 - 51
5X-RAY DIFFRACTION5chain 'B' and (resid 52 through 68 )B52 - 68
6X-RAY DIFFRACTION6chain 'B' and (resid 69 through 75 )B69 - 75
7X-RAY DIFFRACTION7chain 'B' and (resid 76 through 83 )B76 - 83
8X-RAY DIFFRACTION8chain 'B' and (resid 84 through 96 )B84 - 96
9X-RAY DIFFRACTION9chain 'B' and (resid 97 through 139 )B97 - 139
10X-RAY DIFFRACTION10chain 'B' and (resid 140 through 163 )B140 - 163
11X-RAY DIFFRACTION11chain 'B' and (resid 164 through 168 )B164 - 168

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