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- PDB-8zmb: Crystal Structure of the first bromodomain of human BRD4 BD1 in c... -

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Basic information

Entry
Database: PDB / ID: 8zmb
TitleCrystal Structure of the first bromodomain of human BRD4 BD1 in complex with the inhibitor Y13195
ComponentsBRD4_HUMAN
KeywordsPROTEIN BINDING / BRD4 / BD1 / Bromodomain
Function / homology
Function and homology information


RNA polymerase II C-terminal domain binding / P-TEFb complex binding / negative regulation of DNA damage checkpoint / 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 / condensed nuclear chromosome / histone reader activity / : ...RNA polymerase II C-terminal domain binding / P-TEFb complex binding / negative regulation of DNA damage checkpoint / 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 / condensed nuclear chromosome / histone reader activity / : / positive regulation of transcription elongation by RNA polymerase II / transcription coregulator activity / p53 binding / chromosome / regulation of inflammatory response / histone binding / Potential therapeutics for SARS / positive regulation of canonical NF-kappaB signal transduction / transcription coactivator activity / transcription cis-regulatory region binding / chromatin remodeling / protein serine/threonine kinase activity / DNA damage response / chromatin binding / regulation of transcription by RNA polymerase II / chromatin / 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 I / Brdt, bromodomain, repeat II / NET domain superfamily / NET domain profile. / : / NET domain / Bromodomain extra-terminal - transcription regulation / Bromodomain, conserved site ...Bromodomain protein 4, C-terminal / C-terminal domain of bromodomain protein 4 / Brdt, bromodomain, repeat I / Brdt, bromodomain, repeat II / NET domain superfamily / NET domain profile. / : / 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
: / PHOSPHATE ION / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.79 Å
AuthorsLi, J. / Hu, Q. / Xu, H. / Zhao, X. / Zhang, C. / Zhu, R. / 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: 2024
Title: Discovery of the First BRD4 Second Bromodomain (BD2)-Selective Inhibitors.
Authors: Li, J. / Hu, Q. / Zhu, R. / Dong, R. / Shen, H. / Hu, J. / Zhang, C. / Zhang, X. / Xu, T. / Xiang, Q. / Zhang, Y. / Lin, B. / Zhao, L. / Wu, X. / Xu, Y.
History
DepositionMay 22, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Dec 11, 2024Provider: repository / Type: Initial release
Revision 1.1Dec 25, 2024Group: 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: BRD4_HUMAN
B: BRD4_HUMAN
C: BRD4_HUMAN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,51212
Polymers50,3023
Non-polymers2,2109
Water181
1
A: BRD4_HUMAN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,5995
Polymers16,7671
Non-polymers8324
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: BRD4_HUMAN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,5825
Polymers16,7671
Non-polymers8154
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: BRD4_HUMAN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,3312
Polymers16,7671
Non-polymers5641
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)140.990, 140.990, 132.270
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number178
Space group name H-MP6122
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-ID
11
22
33
/ NCS ensembles :
ID
1
2
3

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Components

#1: Protein BRD4_HUMAN / 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 (E. coli) / References: UniProt: O60885
#2: Chemical ChemComp-A1L0Y / 7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methyl-2-(2-phenyl-1H-imidazol-5-yl)furo[3,2-c]pyridin-4(5H)-one


Mass: 563.618 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C34H30FN3O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: PO4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 3.77 Å3/Da / Density % sol: 67.39 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / Details: 0.1 M BIS-TRIS pH 6.5, 2.0 M Ammonium sulfate

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Data collection

DiffractionMean temperature: 80 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 0.97861 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Dec 22, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97861 Å / Relative weight: 1
ReflectionResolution: 2.79→37.41 Å / Num. obs: 19901 / % possible obs: 100 % / Redundancy: 22.4 % / CC1/2: 1 / Rmerge(I) obs: 0.129 / Rpim(I) all: 0.027 / Rrim(I) all: 0.132 / Χ2: 0.95 / Net I/σ(I): 20
Reflection shellResolution: 2.79→2.94 Å / % possible obs: 100 % / Redundancy: 23.4 % / Rmerge(I) obs: 2.819 / Num. measured all: 66722 / Num. unique obs: 2851 / CC1/2: 0.762 / Rpim(I) all: 0.59 / Rrim(I) all: 2.881 / Χ2: 0.92 / Net I/σ(I) obs: 1.2

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Processing

Software
NameVersionClassification
REFMAC5.8.0258refinement
Aimlessdata scaling
xia2data reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7WJS

7wjs


Resolution: 2.79→37.41 Å / Cor.coef. Fo:Fc: 0.963 / Cor.coef. Fo:Fc free: 0.951 / SU B: 18.517 / SU ML: 0.302 / Cross valid method: THROUGHOUT / ESU R: 0.361 / ESU R Free: 0.27 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24354 976 4.9 %RANDOM
Rwork0.20247 ---
obs0.2044 18887 99.91 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 93.594 Å2
Baniso -1Baniso -2Baniso -3
1--5.22 Å2-2.61 Å2-0 Å2
2---5.22 Å20 Å2
3---16.92 Å2
Refinement stepCycle: 1 / Resolution: 2.79→37.41 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2736 0 153 1 2890
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0132970
X-RAY DIFFRACTIONr_bond_other_d0.0010.0172694
X-RAY DIFFRACTIONr_angle_refined_deg1.3981.724053
X-RAY DIFFRACTIONr_angle_other_deg1.1241.6226255
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8025321
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.49525.102147
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.25215513
X-RAY DIFFRACTIONr_dihedral_angle_4_deg10.096156
X-RAY DIFFRACTIONr_chiral_restr0.0560.2363
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.023168
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02594
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it5.9299.6971293
X-RAY DIFFRACTIONr_mcbond_other5.9099.6951292
X-RAY DIFFRACTIONr_mcangle_it9.03214.5381611
X-RAY DIFFRACTIONr_mcangle_other9.03214.5431612
X-RAY DIFFRACTIONr_scbond_it6.52810.2671677
X-RAY DIFFRACTIONr_scbond_other6.36510.2321666
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other9.86115.1292425
X-RAY DIFFRACTIONr_long_range_B_refined12.5033520
X-RAY DIFFRACTIONr_long_range_B_other12.5013521
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.07 Å / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumber
11A3650
12B3650
21A3640
22C3640
31B3639
32C3639
LS refinement shellResolution: 2.79→2.862 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.451 72 -
Rwork0.423 1367 -
obs--99.93 %

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