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- PDB-6c7q: BRD4 BD2 in complex with compound CE277 -

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Basic information

Entry
Database: PDB / ID: 6c7q
TitleBRD4 BD2 in complex with compound CE277
ComponentsBromodomain-containing protein 4BRD4
Keywordstranscription/transcription inhibitor / BROMODOMAIN / TRANSCRIPTION / 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 / 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-EO1 / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.51 Å
AuthorsMeagher, J.L. / Stuckey, J.A.
CitationJournal: J. Med. Chem. / Year: 2018
Title: Structure-Based Discovery of CF53 as a Potent and Orally Bioavailable Bromodomain and Extra-Terminal (BET) Bromodomain Inhibitor.
Authors: Zhao, Y. / Zhou, B. / Bai, L. / Liu, L. / Yang, C.Y. / Meagher, J.L. / Stuckey, J.A. / McEachern, D. / Przybranowski, S. / Wang, M. / Ran, X. / Aguilar, A. / Hu, Y. / Kampf, J.W. / Li, X. / ...Authors: Zhao, Y. / Zhou, B. / Bai, L. / Liu, L. / Yang, C.Y. / Meagher, J.L. / Stuckey, J.A. / McEachern, D. / Przybranowski, S. / Wang, M. / Ran, X. / Aguilar, A. / Hu, Y. / Kampf, J.W. / Li, X. / Zhao, T. / Li, S. / Wen, B. / Sun, D. / Wang, S.
History
DepositionJan 23, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 1, 2018Provider: repository / Type: Initial release
Revision 1.1Aug 8, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Apr 3, 2024Group: 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
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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,7202
Polymers15,2671
Non-polymers4531
Water1,74797
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)52.176, 72.647, 32.222
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212

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Components

#1: Protein Bromodomain-containing protein 4 / BRD4 / Protein HUNK1


Mass: 15266.552 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-EO1 / 7-(3,5-dimethyl-1,2-oxazol-4-yl)-6-methoxy-2-methyl-N-(1-methyl-1H-indazol-3-yl)-9H-pyrimido[4,5-b]indol-4-amine


Mass: 453.496 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H23N7O2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 97 / 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 Å3/Da / Density % sol: 38.5 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8 / Details: 50-75% peg 400, 0.1M Imidizole, pH 8.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-G / Wavelength: 0.9786 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Apr 16, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9786 Å / Relative weight: 1
ReflectionResolution: 1.51→50 Å / Num. obs: 20228 / % possible obs: 99.9 % / Redundancy: 7.7 % / Biso Wilson estimate: 18.33 Å2 / Rmerge(I) obs: 0.067 / Rpim(I) all: 0.026 / Rrim(I) all: 0.072 / Χ2: 1.271 / Net I/σ(I): 10.3 / Num. measured all: 155027
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.51-1.545.80.32410050.9250.1430.3560.93398.7
1.54-1.566.60.39590.960.1260.3270.956100
1.56-1.597.10.27610150.9670.1120.2981.033100
1.59-1.637.90.2469920.970.0930.2631.047100
1.63-1.6680.2229800.9750.0840.2381.166100
1.66-1.78.10.20210200.980.0760.2161.213100
1.7-1.7480.1939770.9760.0740.2071.299100
1.74-1.7980.1719930.9850.0650.1831.34100
1.79-1.847.90.1559850.9870.060.1671.402100
1.84-1.980.14310120.9880.0540.1531.478100
1.9-1.977.80.1279930.9930.0490.1361.557100
1.97-2.057.70.11910140.9930.0460.1281.669100
2.05-2.147.60.10610040.9920.0420.1141.725100
2.14-2.267.60.0989940.9950.0380.1051.667100
2.26-2.47.80.08810220.9940.0340.0951.6100
2.4-2.5880.07910280.9960.030.0851.44100
2.58-2.8480.06710100.9980.0250.0711.223100
2.84-3.2580.0610510.9970.0230.0641.121100
3.25-4.180.04410530.9990.0170.0470.832100
4.1-507.30.03711210.9990.0140.040.6399.4

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Processing

Software
NameVersionClassification
HKL-2000data reduction
HKL-2000data scaling
BUSTER2.10.3refinement
PDB_EXTRACT3.24data extraction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: Previously solved structure in lab

Resolution: 1.51→42.38 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.927 / SU R Cruickshank DPI: 0.074 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.079 / SU Rfree Blow DPI: 0.081 / SU Rfree Cruickshank DPI: 0.077
RfactorNum. reflection% reflectionSelection details
Rfree0.225 1016 5.03 %RANDOM
Rwork0.192 ---
obs0.193 20189 99.5 %-
Displacement parametersBiso max: 90.38 Å2 / Biso mean: 22.29 Å2 / Biso min: 11.16 Å2
Baniso -1Baniso -2Baniso -3
1--3.7767 Å20 Å20 Å2
2--3.799 Å20 Å2
3----0.0223 Å2
Refine analyzeLuzzati coordinate error obs: 0.19 Å
Refinement stepCycle: final / Resolution: 1.51→42.38 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms911 0 41 97 1049
Biso mean--38.28 36.59 -
Num. residues----112
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d334SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes23HARMONIC2
X-RAY DIFFRACTIONt_gen_planes194HARMONIC5
X-RAY DIFFRACTIONt_it987HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion115SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact1245SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d987HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg1336HARMONIC20.9
X-RAY DIFFRACTIONt_omega_torsion3.36
X-RAY DIFFRACTIONt_other_torsion15.57
LS refinement shellResolution: 1.5→1.58 Å / Rfactor Rfree error: 0 / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.2088 151 5.38 %
Rwork0.1701 2657 -
all0.1721 2808 -
obs--96.39 %
Refinement TLS params.Method: refined / Origin x: 9.8914 Å / Origin y: 2.5207 Å / Origin z: 0.4914 Å
111213212223313233
T-0.0199 Å2-0.0019 Å2-0.0047 Å2--0.0148 Å2-0.0021 Å2---0.0344 Å2
L0.6799 °20.0719 °20.0415 °2-1.2439 °2-0.1096 °2--0.475 °2
S0.0007 Å °0.0243 Å °-0.0446 Å °-0.0134 Å °-0.0069 Å °-0.0175 Å °-0.0085 Å °0.0295 Å °0.0062 Å °
Refinement TLS groupSelection details: { A|* }

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