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- PDB-8zm8: Crystal Structure of the first bromodomain of human BRD4 BD1 in c... -

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Basic information

Entry
Database: PDB / ID: 8zm8
TitleCrystal Structure of the first bromodomain of human BRD4 BD1 in complex with the inhibitor Y13221
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 / histone H4 reader activity / host-mediated suppression of viral transcription / positive regulation of G2/M transition of mitotic cell cycle / positive regulation of T-helper 17 cell lineage commitment / : / RNA polymerase II CTD heptapeptide repeat kinase activity / condensed nuclear chromosome ...RNA polymerase II C-terminal domain binding / P-TEFb complex binding / negative regulation of DNA damage checkpoint / histone H4 reader activity / host-mediated suppression of viral transcription / positive regulation of G2/M transition of mitotic cell cycle / positive regulation of T-helper 17 cell lineage commitment / : / RNA polymerase II CTD heptapeptide repeat kinase activity / condensed nuclear chromosome / transcription coregulator activity / positive regulation of transcription elongation by RNA polymerase II / p53 binding / chromosome / regulation of inflammatory response / histone binding / Potential therapeutics for SARS / transcription coactivator activity / positive regulation of canonical NF-kappaB signal transduction / 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 / bromo domain / Bromodomain / Bromodomain (BrD) profile. / Bromodomain-like superfamily
Similarity search - Domain/homology
: / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3 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)51,9816
Polymers50,3023
Non-polymers1,6793
Water362
1
A: BRD4_HUMAN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,3272
Polymers16,7671
Non-polymers5601
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: BRD4_HUMAN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,3272
Polymers16,7671
Non-polymers5601
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: BRD4_HUMAN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,3272
Polymers16,7671
Non-polymers5601
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)142.067, 142.067, 134.141
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number178
Space group name H-MP6122

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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
Details: BRD4_HUMAN, O60885, sequence from 28-43 are tags. MKKGHHHHHHLVPRGS
Source: (gene. exp.) Homo sapiens (human) / Gene: BRD4, HUNK1 / Production host: Escherichia coli (E. coli) / References: UniProt: O60885
#2: Chemical ChemComp-A1L1X / 2-[2-ethyl-4-(methoxymethyl)-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: 559.628 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C32H34FN3O5 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 2 / 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: 3.88 Å3/Da / Density % sol: 68.33 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 1.0 M Sodium phosphate monobasic monohydrate, Potassium phosphate dibasic / pH 8.2
PH range: 8.2

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Data collection

DiffractionMean temperature: 80 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL02U1 / Wavelength: 0.97918 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jan 26, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 3→123.03 Å / Num. obs: 16573 / % possible obs: 100 % / Redundancy: 18.8 % / CC1/2: 0.998 / Rmerge(I) obs: 0.167 / Rpim(I) all: 0.039 / Rrim(I) all: 0.172 / Χ2: 0.99 / Net I/σ(I): 12.4 / Num. measured all: 311428
Reflection shellResolution: 3→3.18 Å / % possible obs: 100 % / Redundancy: 19.6 % / Rmerge(I) obs: 1.53 / Num. measured all: 51074 / Num. unique obs: 2607 / CC1/2: 0.882 / Rpim(I) all: 0.352 / Rrim(I) all: 1.571 / Χ2: 1 / Net I/σ(I) obs: 2.2

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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: 3→123.03 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.904 / SU B: 18.995 / SU ML: 0.299 / Cross valid method: THROUGHOUT / ESU R: 0.525 / ESU R Free: 0.346 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.26451 863 5.2 %RANDOM
Rwork0.20655 ---
obs0.20962 15660 99.88 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 92.681 Å2
Baniso -1Baniso -2Baniso -3
1--4.75 Å2-2.38 Å2-0 Å2
2---4.75 Å20 Å2
3---15.42 Å2
Refinement stepCycle: 1 / Resolution: 3→123.03 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2732 0 123 2 2857
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0132955
X-RAY DIFFRACTIONr_bond_other_d0.0010.0182695
X-RAY DIFFRACTIONr_angle_refined_deg1.4721.7194031
X-RAY DIFFRACTIONr_angle_other_deg1.1071.6336260
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3515321
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.39924.933150
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.77915512
X-RAY DIFFRACTIONr_dihedral_angle_4_deg11.982157
X-RAY DIFFRACTIONr_chiral_restr0.0550.2365
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.023160
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02581
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_it5.3099.6821299
X-RAY DIFFRACTIONr_mcbond_other5.2849.681298
X-RAY DIFFRACTIONr_mcangle_it8.38914.4861615
X-RAY DIFFRACTIONr_mcangle_other8.39114.491616
X-RAY DIFFRACTIONr_scbond_it5.28910.1561656
X-RAY DIFFRACTIONr_scbond_other5.28910.1581657
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other8.67915.0572417
X-RAY DIFFRACTIONr_long_range_B_refined12.3523484
X-RAY DIFFRACTIONr_long_range_B_other12.3543485
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 3→3.078 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.4 53 -
Rwork0.34 1139 -
obs--99.92 %

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