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- PDB-5jwm: Bivalent BET Bromodomain Inhibition -

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Basic information

Entry
Database: PDB / ID: 5jwm
TitleBivalent BET Bromodomain Inhibition
ComponentsBromodomain-containing protein 4BRD4
Keywordstranscription/transcription inhibitor / bivalent-ligand / bromodomain / inhibitor / 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-6ON / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.71 Å
AuthorsSeo, H.-S. / Dhe-Paganon, S.
CitationJournal: Nat.Chem.Biol. / Year: 2016
Title: Design and characterization of bivalent BET inhibitors.
Authors: Tanaka, M. / Roberts, J.M. / Seo, H.S. / Souza, A. / Paulk, J. / Scott, T.G. / DeAngelo, S.L. / Dhe-Paganon, S. / Bradner, J.E.
History
DepositionMay 12, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 6, 2016Provider: repository / Type: Initial release
Revision 1.1Oct 19, 2016Group: Database references
Revision 1.2Nov 9, 2016Group: Database references
Revision 1.3Nov 23, 2016Group: Database references
Revision 1.4Sep 27, 2023Group: 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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)31,2553
Polymers30,1212
Non-polymers1,1341
Water3,693205
1
A: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)16,1952
Polymers15,0601
Non-polymers1,1341
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Bromodomain-containing protein 4


Theoretical massNumber of molelcules
Total (without water)15,0601
Polymers15,0601
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)75.670, 107.140, 74.840
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11A-645-

HOH

21B-507-

HOH

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Components

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


Mass: 15060.332 Da / Num. of mol.: 2 / Fragment: unp residues 333-460
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-6ON / 2-[(9~{S})-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.0^{2,6}]trideca-2(6),4,7,10,12-pentaen-9-yl]-~{N}-[2-[2-[2-[2-[2-[2-[2-[2-[2-[(9~{S})-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.0^{2,6}]trideca-2(6),4,7,10,12-pentaen-9-yl]ethanoylamino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]ethanamide


Mass: 1134.199 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C54H66Cl2N10O9S2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 205 / 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: 2.52 Å3/Da / Density % sol: 51.15 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 5.5 / Details: 2M ammonium sulfate, 0.1M BisTris (pH 5.5)

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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: Oct 22, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9792 Å / Relative weight: 1
ReflectionResolution: 1.71→43.56 Å / Num. obs: 32881 / % possible obs: 99.1 % / Redundancy: 3.6 % / CC1/2: 0.999 / Rmerge(I) obs: 0.046 / Rpim(I) all: 0.027 / Rrim(I) all: 0.054 / Net I/σ(I): 16.8 / Num. measured all: 119782 / Scaling rejects: 28
Reflection shell

Diffraction-ID: 1 / Rejects: 0

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique allCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
1.71-1.753.70.658891624400.7190.4020.7752.299.5
7.65-43.5630.03411553790.9960.0230.04142.391.8

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
PHENIX1.10_2155refinement
Aimless0.5.23data scaling
PHASERphasing
PDB_EXTRACT3.2data extraction
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3MXF

3mxf


Resolution: 1.71→43.561 Å / SU ML: 0.14 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 16.54 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1675 1586 4.82 %
Rwork0.1448 31290 -
obs0.1459 32876 98.91 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 94.77 Å2 / Biso mean: 34.8204 Å2 / Biso min: 17.33 Å2
Refinement stepCycle: final / Resolution: 1.71→43.561 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1777 0 143 205 2125
Biso mean--42.31 40.78 -
Num. residues----220
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0091924
X-RAY DIFFRACTIONf_angle_d1.442593
X-RAY DIFFRACTIONf_chiral_restr0.051255
X-RAY DIFFRACTIONf_plane_restr0.007329
X-RAY DIFFRACTIONf_dihedral_angle_d15.291176
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 11

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.71-1.76520.23391480.1982814296299
1.7652-1.82830.24911530.18342821297499
1.8283-1.90150.21181440.169228252969100
1.9015-1.9880.19491370.147428683005100
1.988-2.09290.16621350.137228232958100
2.0929-2.2240.19111430.127728392982100
2.224-2.39570.19111470.132840298799
2.3957-2.63670.1691570.13762835299299
2.6367-3.01820.1591280.13952882301099
3.0182-3.80230.14551540.14032846300098
3.8023-43.57470.14971400.15132897303795

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