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

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Basic information

Entry
Database: PDB / ID: 4wiv
TitleCrystal Structure of the first bromodomain of human BRD4 in complex with a novel inhibitor UMB32 (N-TERT-BUTYL-2-[4-(3,5-DIMETHYL-1,2-OXAZOL-4-YL) PHENYL]IMIDAZO[1,2-A]PYRAZIN-3-AMINE)
ComponentsBromodomain-containing protein 4
Keywordstranscription/transcription inhibitor / Drug Discovery / Epigenesis / Structure-Activity Relationship / Tumor / 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 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-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-3P2 / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.56 Å
AuthorsXu, X. / Blacklow, S.
CitationJournal: J.Med.Chem. / Year: 2014
Title: Biased multicomponent reactions to develop novel bromodomain inhibitors.
Authors: McKeown, M.R. / Shaw, D.L. / Fu, H. / Liu, S. / Xu, X. / Marineau, J.J. / Huang, Y. / Zhang, X. / Buckley, D.L. / Kadam, A. / Zhang, Z. / Blacklow, S.C. / Qi, J. / Zhang, W. / Bradner, J.E.
History
DepositionSep 26, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 29, 2014Provider: repository / Type: Initial release
Revision 1.1Nov 26, 2014Group: Database references
Revision 1.2Feb 4, 2015Group: Derived calculations
Revision 1.3Aug 26, 2015Group: Other
Revision 1.4Sep 27, 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_oper_list
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation

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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)15,7696
Polymers15,0991
Non-polymers6705
Water2,774154
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)43.562, 49.210, 60.991
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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 / Fragment: unp 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) / Strain (production host): BL21(DE3) / References: UniProt: O60885
#2: Chemical ChemComp-3P2 / N-tert-butyl-2-[4-(3,5-dimethyl-1,2-oxazol-4-yl)phenyl]imidazo[1,2-a]pyrazin-3-amine


Mass: 361.440 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H23N5O
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 154 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.2 Å3/Da / Density % sol: 44.6 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop / pH: 7.4
Details: Crystals of inhibitor-free BRD4-BD1 were first obtained in a drop with equal volumes of BD1 at 12 mg/ml and a precipitant solution containing 100mM sodium nitrate, 5% ethylene glycol, and ...Details: Crystals of inhibitor-free BRD4-BD1 were first obtained in a drop with equal volumes of BD1 at 12 mg/ml and a precipitant solution containing 100mM sodium nitrate, 5% ethylene glycol, and 18% (w/v) PEG3350, as precipitant. Rod-like crystals were typically grown in 10 days reaching a maximal size of 0.05x0.05x0.4 mm3. Then, native crystals were transferred and soaked in 1 mM UMB32 in the same crystallization buffer for 7 days.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.9792 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Feb 14, 2014
RadiationMonochromator: Si(311) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9792 Å / Relative weight: 1
ReflectionResolution: 1.56→35.45 Å / Num. obs: 19177 / % possible obs: 99.58 % / Redundancy: 3.9 % / Biso Wilson estimate: 14.04 Å2 / Net I/σ(I): 9.88
Reflection shellResolution: 1.56→1.616 Å / Redundancy: 3.9 % / Mean I/σ(I) obs: 1.62 / % possible all: 100

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Processing

SoftwareName: PHENIX / Version: (phenix.refine: 1.9_1678) / Classification: refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3MXF

3mxf


Resolution: 1.56→35.449 Å / SU ML: 0.14 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 19.06 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2013 986 5.14 %Random selectio
Rwork0.1698 ---
obs0.1714 19175 99.57 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 19.6 Å2
Refinement stepCycle: LAST / Resolution: 1.56→35.449 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1047 0 47 154 1248
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0071123
X-RAY DIFFRACTIONf_angle_d1.2961526
X-RAY DIFFRACTIONf_dihedral_angle_d11.847422
X-RAY DIFFRACTIONf_chiral_restr0.038159
X-RAY DIFFRACTIONf_plane_restr0.005192
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.56-1.64230.29051450.24952542X-RAY DIFFRACTION100
1.6423-1.74510.21171280.21752583X-RAY DIFFRACTION100
1.7451-1.87990.23381480.19052558X-RAY DIFFRACTION100
1.8799-2.0690.21161570.15672559X-RAY DIFFRACTION100
2.069-2.36840.18271330.14722586X-RAY DIFFRACTION99
2.3684-2.98370.18741580.16542598X-RAY DIFFRACTION99
2.9837-35.45780.18861170.16082763X-RAY DIFFRACTION99
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)
12.9079-0.76291.68652.6828-0.39093.5655-0.0176-0.01570.00330.00780.1328-0.1517-0.00790.1799-0.09940.11070.00110.02440.1275-0.01470.117217.216-7.8784-25.5832
26.3589-0.553-1.37680.930.14041.0823-0.21230.2627-0.0031-0.0880.0885-0.0136-0.0566-0.07240.04890.1417-0.01540.00940.129-0.00870.11010.9896-7.0104-36.9273
33.04651.00531.43161.22651.64663.004-0.0803-0.05740.4053-0.0507-0.1340.1942-0.1071-0.17030.17440.11610.0123-0.00220.1157-0.03110.1742-4.50430.6304-22.0518
42.3904-1.1143-0.03032.36390.03071.6587-0.051-0.25590.14760.09530.0864-0.1231-0.02950.13890.0090.1095-0.005-0.0110.1326-0.04010.12313.5677-3.0843-12.1012
51.6527-0.46110.75671.6064-0.62031.74960.0151-0.00880.08490.0957-0.03060.0388-0.03720.13210.02390.09840.00350.00920.098-0.01630.099110.0055-8.0999-21.1135
63.17221.67980.9271.71051.65752.04830.07080.27210.1677-0.0866-0.2006-0.0318-0.0367-0.0950.13970.10030.012-0.00650.13110.02120.10580.1948-6.0607-32.2738
71.3943-0.96451.23511.0163-1.10451.9453-0.0049-0.1088-0.04170.00270.05690.01560.0659-0.093-0.05380.1216-0.00310.01430.1081-0.00490.10813.367-11.8109-17.5019
80.09730.01680.34622.0011.20432.2064-0.0642-0.6327-0.12851.16920.13780.01140.4122-0.2096-0.03270.33980.00450.0170.28940.04770.143710.321-12.5038-2.666
93.6408-0.58621.50031.0781-0.47012.0069-0.1347-0.6909-0.26740.20190.17960.22030.0298-0.50.00570.1530.00610.05370.2225-0.03560.1575-1.9644-5.6684-9.6746
109.09421.03213.22265.0193.07878.8403-0.06830.29540.1499-0.81050.46770.5729-0.0756-0.0958-0.22150.1947-0.0578-0.04810.2629-0.00980.2508-14.498-5.3266-26.0194
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 42 through 51 )
2X-RAY DIFFRACTION2chain 'A' and (resid 52 through 60 )
3X-RAY DIFFRACTION3chain 'A' and (resid 61 through 75 )
4X-RAY DIFFRACTION4chain 'A' and (resid 76 through 96 )
5X-RAY DIFFRACTION5chain 'A' and (resid 97 through 115 )
6X-RAY DIFFRACTION6chain 'A' and (resid 116 through 121 )
7X-RAY DIFFRACTION7chain 'A' and (resid 122 through 139 )
8X-RAY DIFFRACTION8chain 'A' and (resid 140 through 144 )
9X-RAY DIFFRACTION9chain 'A' and (resid 145 through 163 )
10X-RAY DIFFRACTION10chain 'A' and (resid 164 through 168 )

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