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- PDB-7wjs: Crystal Structure of the first bromodomain of human BRD4 in compl... -

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Basic information

Entry
Database: PDB / ID: 7wjs
TitleCrystal Structure of the first bromodomain of human BRD4 in complex with the inhibitor Y13157
ComponentsBromodomain-containing protein 4
KeywordsPROTEIN BINDING / BRD4 / Bromodomain / Inhibitor
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, conserved site / Bromodomain signature. ...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, conserved site / Bromodomain signature. / Bromodomain / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily
Similarity search - Domain/homology
Chem-JFL / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.73 Å
AuthorsLi, J. / Zhang, C. / Xu, H. / Zhuang, X. / Wu, X. / Zhang, Y. / Xu, Y.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)81673357 China
CitationJournal: J.Med.Chem. / Year: 2022
Title: Structure-Based Discovery and Optimization of Furo[3,2- c ]pyridin-4(5 H )-one Derivatives as Potent and Second Bromodomain (BD2)-Selective Bromo and Extra Terminal Domain (BET) Inhibitors.
Authors: Li, J. / Zhang, C. / Xu, H. / Wang, C. / Dong, R. / Shen, H. / Zhuang, X. / Chen, X. / Li, Q. / Lu, J. / Zhang, M. / Wu, X. / Loomes, K.M. / Zhou, Y. / Zhang, Y. / Liu, J. / Xu, Y.
History
DepositionJan 7, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Aug 10, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Bromodomain-containing protein 4
B: Bromodomain-containing protein 4
C: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,75615
Polymers50,3023
Non-polymers2,45412
Water32418
1
A: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,5855
Polymers16,7671
Non-polymers8184
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area400 Å2
ΔGint-2 kcal/mol
Surface area6870 Å2
MethodPISA
2
B: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,5855
Polymers16,7671
Non-polymers8184
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area260 Å2
ΔGint-1 kcal/mol
Surface area6830 Å2
MethodPISA
3
C: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,5855
Polymers16,7671
Non-polymers8184
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area530 Å2
ΔGint-2 kcal/mol
Surface area6930 Å2
MethodPISA
Unit cell
Length a, b, c (Å)141.205, 141.205, 132.727
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number178
Space group name H-MP6122

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Components

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


Mass: 16767.326 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRD4, HUNK1 / Production host: Escherichia coli BL21 (bacteria) / References: UniProt: O60885
#2: Chemical ChemComp-JFL / 2-(2-cyclobutyl-1~{H}-imidazol-5-yl)-7-[2-(4-fluoranyl-2,6-dimethyl-phenoxy)-5-(2-oxidanylpropan-2-yl)phenyl]-5-methyl-furo[3,2-c]pyridin-4-one


Mass: 541.613 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C32H32FN3O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 18 / 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: 3.8 Å3/Da / Density % sol: 67.6 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7
Details: 1.5 M Lithium sulfate monohydrate, 0.1 M BIS-TRIS propane pH 7.0

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Data collection

DiffractionMean temperature: 197 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL02U1 / Wavelength: 0.97911 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Oct 5, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97911 Å / Relative weight: 1
ReflectionResolution: 2.73→44.97 Å / Num. obs: 21133 / % possible obs: 99.4 % / Redundancy: 5.4 % / CC1/2: 0.997 / Rmerge(I) obs: 0.083 / Rpim(I) all: 0.039 / Rrim(I) all: 0.092 / Net I/σ(I): 12.9
Reflection shell

Diffraction-ID: 1 / Resolution: 2.73→2.86 Å

Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
5.20.74727600.8290.3630.833100
4.90.056120.9970.0240.05692.8

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Processing

Software
NameVersionClassification
Aimless0.5.32data scaling
REFMAC5.8.0189refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6viw

6viw


Resolution: 2.73→44.97 Å / Cor.coef. Fo:Fc: 0.964 / Cor.coef. Fo:Fc free: 0.951 / SU B: 9.916 / SU ML: 0.183 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.297 / ESU R Free: 0.228 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2149 1045 5 %RANDOM
Rwork0.1809 ---
obs0.1826 20064 99.11 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 183.15 Å2 / Biso mean: 79.584 Å2 / Biso min: 45.5 Å2
Baniso -1Baniso -2Baniso -3
1--2.84 Å2-1.42 Å2-0 Å2
2---2.84 Å2-0 Å2
3---9.21 Å2
Refinement stepCycle: final / Resolution: 2.73→44.97 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2724 0 174 18 2916
Biso mean--89.37 63.46 -
Num. residues----323
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.022976
X-RAY DIFFRACTIONr_bond_other_d0.0020.022722
X-RAY DIFFRACTIONr_angle_refined_deg1.4622.0194050
X-RAY DIFFRACTIONr_angle_other_deg1.0933.0096334
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.5185320
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.55525.714140
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.89115508
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.825156
X-RAY DIFFRACTIONr_chiral_restr0.0750.2428
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0213130
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02572
LS refinement shellResolution: 2.73→2.801 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.327 77 -
Rwork0.322 1441 -
all-1518 -
obs--99.93 %

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