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- PDB-4hbw: Crystal Structure of the first bromodomain of human BRD4 in compl... -

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Basic information

Entry
Database: PDB / ID: 4hbw
TitleCrystal Structure of the first bromodomain of human BRD4 in complex with a quinazoline ligand
ComponentsBromodomain-containing protein 4
KeywordsPROTEIN BINDING/INHIBITOR / BROMODOMAIN / CAP / HUNK1 / MCAP / PROTEIN BINDING-INHIBITOR COMPLEX / MITOTIC CHROMOSOME ASSOCIATED PROTEIN / CELL CYCLE / STRUCTURAL GENOMICS CONSORTIUM / SGC
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 / RNA polymerase II CTD heptapeptide repeat kinase activity / histone reader 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 / RNA polymerase II CTD heptapeptide repeat kinase activity / histone reader 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 / Brdt, bromodomain, repeat II / Brdt, bromodomain, repeat I / NET domain superfamily / NET domain profile. / : / NET domain / Bromodomain extra-terminal - transcription regulation / Bromodomain-like ...Bromodomain protein 4, C-terminal / C-terminal domain of bromodomain protein 4 / Brdt, bromodomain, repeat II / Brdt, bromodomain, repeat I / NET domain superfamily / NET domain profile. / : / 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-14Z / : / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.69 Å
AuthorsFilippakopoulos, P. / Picaud, S. / Qi, J. / Felletar, I. / von Delft, F. / Bountra, C. / Arrowsmith, C.H. / Edwards, A. / Fish, P.V. / Bunnage, M.E. ...Filippakopoulos, P. / Picaud, S. / Qi, J. / Felletar, I. / von Delft, F. / Bountra, C. / Arrowsmith, C.H. / Edwards, A. / Fish, P.V. / Bunnage, M.E. / Cook, A.S. / Owen, D.R. / Knapp, S. / Structural Genomics Consortium (SGC)
CitationJournal: J.Med.Chem. / Year: 2012
Title: Identification of a Chemical Probe for Bromo and Extra C-Terminal Bromodomain Inhibition through Optimization of a Fragment-Derived Hit.
Authors: Fish, P.V. / Filippakopoulos, P. / Bish, G. / Brennan, P.E. / Bunnage, M.E. / Cook, A.S. / Federov, O. / Gerstenberger, B.S. / Jones, H. / Knapp, S. / Marsden, B. / Nocka, K. / Owen, D.R. / ...Authors: Fish, P.V. / Filippakopoulos, P. / Bish, G. / Brennan, P.E. / Bunnage, M.E. / Cook, A.S. / Federov, O. / Gerstenberger, B.S. / Jones, H. / Knapp, S. / Marsden, B. / Nocka, K. / Owen, D.R. / Philpott, M. / Picaud, S. / Primiano, M.J. / Ralph, M.J. / Sciammetta, N. / Trzupek, J.D.
History
DepositionSep 28, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 31, 2012Provider: repository / Type: Initial release
Revision 1.1Nov 14, 2012Group: Database references
Revision 1.2Dec 12, 2012Group: Database references
Revision 1.3Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,4714
Polymers15,1001
Non-polymers3703
Water3,063170
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)36.650, 46.020, 77.310
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: 15100.364 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRD4, HUNK1 / Plasmid: pNIC28-Bsa4 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)-R3 / References: UniProt: O60885
#2: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#3: Chemical ChemComp-14Z / N-ethyl-3-methyl-2-oxo-1,2,3,4-tetrahydroquinazoline-6-sulfonamide


Mass: 269.320 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H15N3O3S
#4: Chemical ChemComp-K / POTASSIUM ION


Mass: 39.098 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: K
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 170 / 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: 2.16 Å3/Da / Density % sol: 43.02 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 0.20M K3(cit), 0.1M BTProp pH 8.5, 20.0% PEG 3350, 10.0% EtGly, VAPOR DIFFUSION, SITTING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Nov 3, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionRedundancy: 4.5 % / Av σ(I) over netI: 4.6 / Number: 69901 / Rsym value: 0.097 / D res high: 1.685 Å / D res low: 29.599 Å / Num. obs: 15402 / % possible obs: 100
Diffraction reflection shell
Highest resolution (Å)Lowest resolution (Å)% possible obs (%)IDRmerge(I) obsRsym valueRedundancy
5.3329.699.510.0710.0714.1
3.775.3310010.0690.0694.5
3.083.7710010.0770.0774.6
2.663.0810010.0840.0844.7
2.382.6610010.0980.0984.6
2.182.3810010.1170.1174.6
2.012.1810010.1520.1524.6
1.882.0110010.2260.2264.6
1.781.8810010.3460.3464.5
1.681.7810010.5920.5924.3
ReflectionResolution: 1.685→29.6 Å / Num. all: 15402 / Num. obs: 15402 / % possible obs: 100 % / Redundancy: 4.5 % / Biso Wilson estimate: 22.2 Å2 / Rmerge(I) obs: 0.097 / Rsym value: 0.097 / Net I/σ(I): 9.1
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRsym value% possible all
1.68-1.784.30.5921.3951821890.592100
1.78-1.884.50.3462.2938520760.346100
1.88-2.014.60.2263.2904519850.226100
2.01-2.184.60.1524.6843118390.152100
2.18-2.384.60.1175.8779716870.117100
2.38-2.664.60.0986.8726015640.098100
2.66-3.084.70.0847.3642813790.084100
3.08-3.774.60.0777.4544811780.077100
3.77-5.334.50.069842879430.069100
5.33-29.5994.10.071623025620.07199.5

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Phasing

PhasingMethod: molecular replacement
Phasing MRRfactor: 55.04 / Model details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation2.5 Å29.6 Å
Translation2.5 Å29.6 Å

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Processing

Software
NameVersionClassificationNB
SCALA3.3.16data scaling
PHASER2.1.4phasing
REFMACrefinement
PDB_EXTRACT3.11data extraction
CrystalCleardata collection
MOSFLMdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2OSS

2oss


Resolution: 1.69→29.6 Å / Cor.coef. Fo:Fc: 0.964 / Cor.coef. Fo:Fc free: 0.944 / WRfactor Rfree: 0.2309 / WRfactor Rwork: 0.1754 / Occupancy max: 1 / Occupancy min: 0.5 / FOM work R set: 0.8781 / SU B: 3.869 / SU ML: 0.069 / SU R Cruickshank DPI: 0.109 / SU Rfree: 0.1153 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.109 / ESU R Free: 0.115 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES: WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2283 767 5 %RANDOM
Rwork0.1744 ---
all0.1769 15359 --
obs0.1769 15356 99.98 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso max: 72.59 Å2 / Biso mean: 20.7642 Å2 / Biso min: 4.84 Å2
Baniso -1Baniso -2Baniso -3
1-1.61 Å20 Å20 Å2
2---0.71 Å20 Å2
3----0.89 Å2
Refinement stepCycle: LAST / Resolution: 1.69→29.6 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1047 0 23 170 1240
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0221129
X-RAY DIFFRACTIONr_bond_other_d0.0010.02772
X-RAY DIFFRACTIONr_angle_refined_deg1.5751.9881544
X-RAY DIFFRACTIONr_angle_other_deg0.9473.0021900
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.1685132
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.99926.36455
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.80515201
X-RAY DIFFRACTIONr_dihedral_angle_4_deg29.497152
X-RAY DIFFRACTIONr_chiral_restr0.3330.2165
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0211216
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02196
X-RAY DIFFRACTIONr_mcbond_it2.5723656
X-RAY DIFFRACTIONr_mcbond_other0.9093246
X-RAY DIFFRACTIONr_mcangle_it3.91951084
X-RAY DIFFRACTIONr_scbond_it6.2068473
X-RAY DIFFRACTIONr_scangle_it7.24311457
LS refinement shellResolution: 1.685→1.729 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.552 52 -
Rwork0.479 1059 -
all-1111 -
obs--99.82 %
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)
10.12930.04680.11850.5015-0.04260.9514-0.0008-0.032-0.00230.1275-0.05750.05620.0063-0.02920.05840.09720.0003-0.00160.0493-0.00940.025229.692427.082218.8967
20.09180.09030.14710.33760.15620.4102-0.0017-0.0131-0.0298-0.0118-0.04080.0665-0.039-0.0170.04250.069-0.0008-0.00690.0555-0.00920.049727.971622.91778.2055
3-0.4352-0.7452-0.44241.52833.54513.32830.0042-0.0210.0217-0.18060.1002-0.1164-0.20250.1705-0.10440.0994-0.0179-0.00310.07570.01520.07934.263632.076611.1718
40.092-0.06060.11491.0110.01730.0995-0.08540.03620.0096-0.02580.03820.0748-0.05420.060.04720.0905-0.0069-0.01720.05690.01210.046731.474130.36570.597
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A42 - 65
2X-RAY DIFFRACTION2A66 - 122
3X-RAY DIFFRACTION3A123 - 130
4X-RAY DIFFRACTION4A131 - 168

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