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- PDB-6wvx: Crystal structure of the first bromodomain of human BRD4 with ben... -

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Basic information

Entry
Database: PDB / ID: 6wvx
TitleCrystal structure of the first bromodomain of human BRD4 with benzodiazepine inhibitor
ComponentsBromodomain-containing protein 4BRD4
KeywordsGENE REGULATION/INHIBITOR / Inhibitor / bromodomain / BRD4 / benzodiazepine / GENE REGULATION / GENE REGULATION-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, 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-UDV / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.55 Å
AuthorsEron, S.J.
CitationJournal: Acs Chem.Biol. / Year: 2021
Title: Structural Characterization of Degrader-Induced Ternary Complexes Using Hydrogen-Deuterium Exchange Mass Spectrometry and Computational Modeling: Implications for Structure-Based Design.
Authors: Eron, S.J. / Huang, H. / Agafonov, R.V. / Fitzgerald, M.E. / Patel, J. / Michael, R.E. / Lee, T.D. / Hart, A.A. / Shaulsky, J. / Nasveschuk, C.G. / Phillips, A.J. / Fisher, S.L. / Good, A.
History
DepositionMay 7, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 1, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 13, 2021Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Dec 1, 2021Group: 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 1.3Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id ..._struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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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)31,1434
Polymers30,3132
Non-polymers8302
Water4,179232
1
A: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,5712
Polymers15,1561
Non-polymers4151
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,5712
Polymers15,1561
Non-polymers4151
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)30.430, 39.710, 57.820
Angle α, β, γ (deg.)82.210, 75.250, 89.860
Int Tables number1
Space group name H-MP1
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Component-ID: 1 / Ens-ID: 1 / Beg auth comp-ID: GLY / Beg label comp-ID: GLY / End auth comp-ID: THR / End label comp-ID: THR / Refine code: 1 / Auth seq-ID: 41 - 166 / Label seq-ID: 1 - 126

Dom-IDAuth asym-IDLabel asym-ID
1AA
2BB

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Components

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


Mass: 15156.431 Da / Num. of mol.: 2
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-UDV / 6'-(4-chlorophenyl)-1'-methyl-8'-(1-methyl-1H-pyrazol-4-yl)spiro[cyclopropane-1,4'-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine]


Mass: 414.890 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H19ClN6 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 232 / 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: 2.21 Å3/Da / Density % sol: 44.4 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / Details: 0.18 M Triammonium Citrate, 20% (w/v) PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: MASSIF-1 / Wavelength: 0.966 Å
DetectorType: DECTRIS PILATUS3 2M / Detector: PIXEL / Date: Nov 23, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.966 Å / Relative weight: 1
ReflectionResolution: 1.55→55.368 Å / Num. obs: 33390 / % possible obs: 88.7 % / Redundancy: 1.5 % / CC1/2: 0.987 / Rmerge(I) obs: 0.089 / Rpim(I) all: 0.089 / Rrim(I) all: 0.126 / Net I/σ(I): 3.2
Reflection shellResolution: 1.55→1.58 Å / Rmerge(I) obs: 0.531 / Num. unique obs: 1696 / CC1/2: 0.601 / Rpim(I) all: 0.531 / Rrim(I) all: 0.751 / % possible all: 90.2

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Processing

Software
NameVersionClassification
REFMAC5.8.0258refinement
XDSdata reduction
Aimless0.7.4data scaling
PHASER2.8.3phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4Z1S

4z1s


Resolution: 1.55→39.32 Å / Cor.coef. Fo:Fc: 0.934 / Cor.coef. Fo:Fc free: 0.918 / SU B: 2.635 / SU ML: 0.093 / Cross valid method: FREE R-VALUE / ESU R: 0.119 / ESU R Free: 0.112
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2462 1681 5.067 %
Rwork0.2168 31495 -
all0.218 --
obs-33176 88.119 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 12.361 Å2
Baniso -1Baniso -2Baniso -3
1--0.658 Å20.002 Å20.489 Å2
2--0.283 Å20.302 Å2
3---0.61 Å2
Refinement stepCycle: LAST / Resolution: 1.55→39.32 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2090 0 60 232 2382
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0132262
X-RAY DIFFRACTIONr_bond_other_d0.0020.0172052
X-RAY DIFFRACTIONr_angle_refined_deg1.5941.6573097
X-RAY DIFFRACTIONr_angle_other_deg1.4311.5984813
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.7865259
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.35524.909110
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.55315394
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.613156
X-RAY DIFFRACTIONr_chiral_restr0.0770.2285
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.022451
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02429
X-RAY DIFFRACTIONr_nbd_refined0.2170.2442
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1830.21801
X-RAY DIFFRACTIONr_nbtor_refined0.1820.21107
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0860.2795
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.160.2144
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.030.21
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2010.26
X-RAY DIFFRACTIONr_nbd_other0.2140.246
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1930.213
X-RAY DIFFRACTIONr_mcbond_it1.0121.1741028
X-RAY DIFFRACTIONr_mcbond_other1.0121.1741029
X-RAY DIFFRACTIONr_mcangle_it1.6771.7511290
X-RAY DIFFRACTIONr_mcangle_other1.6771.7541290
X-RAY DIFFRACTIONr_scbond_it1.5031.2991234
X-RAY DIFFRACTIONr_scbond_other1.5021.2981235
X-RAY DIFFRACTIONr_scangle_it2.3381.8851800
X-RAY DIFFRACTIONr_scangle_other2.3371.8851801
X-RAY DIFFRACTIONr_lrange_it3.59713.5612652
X-RAY DIFFRACTIONr_lrange_other3.51713.2692602
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.55-1.590.2771550.2692367X-RAY DIFFRACTION90.2326
1.59-1.6340.2921320.2582295X-RAY DIFFRACTION89.5242
1.634-1.6810.31260.2432219X-RAY DIFFRACTION88.6914
1.681-1.7330.2641190.2332140X-RAY DIFFRACTION87.5921
1.733-1.790.2811050.2272030X-RAY DIFFRACTION85.6742
1.79-1.8520.238950.2131952X-RAY DIFFRACTION86.5539
1.852-1.9220.378960.3631853X-RAY DIFFRACTION83.0776
1.922-2.0010.284950.2631795X-RAY DIFFRACTION84.6774
2.001-2.0890.253880.221832X-RAY DIFFRACTION90.3955
2.089-2.1910.239790.2071822X-RAY DIFFRACTION92.0581
2.191-2.310.399850.3121541X-RAY DIFFRACTION84.6875
2.31-2.4490.215860.1881544X-RAY DIFFRACTION89.659
2.449-2.6180.247760.1821483X-RAY DIFFRACTION88.984
2.618-2.8270.1891030.1921343X-RAY DIFFRACTION90.3186
2.827-3.0960.202580.1891243X-RAY DIFFRACTION87.4328
3.096-3.4610.189550.1861108X-RAY DIFFRACTION87.3779
3.461-3.9930.197490.1631007X-RAY DIFFRACTION89.3401
3.993-4.8840.169440.159878X-RAY DIFFRACTION92.016
4.884-6.8810.206230.192665X-RAY DIFFRACTION90.8851
6.881-39.320.241120.205377X-RAY DIFFRACTION87.8104

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