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- PDB-3uvx: Crystal Structure of the first bromodomain of human BRD4 in compl... -

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Basic information

Entry
Database: PDB / ID: 3uvx
TitleCrystal Structure of the first bromodomain of human BRD4 in complex with a diacetylated histone 4 peptide (H4K12acK16ac)
Components
  • Bromodomain-containing protein 4
  • diacetylated histone 4 peptide
KeywordsTRANSCRIPTION/PROTEIN BINDING / Bromodomain / Bromodomain containing protein 4 / CAP / HUNK1 / MCAP / Mitotic chromosome associated protein / peptide complex / Structural Genomics Consortium / SGC / TRANSCRIPTION-PROTEIN BINDING 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 / negative regulation of megakaryocyte differentiation / protein localization to CENP-A containing chromatin / Replacement of protamines by nucleosomes in the male pronucleus / CENP-A containing nucleosome / positive regulation of T-helper 17 cell lineage commitment / Packaging Of Telomere Ends ...RNA polymerase II C-terminal domain binding / negative regulation of DNA damage checkpoint / P-TEFb complex binding / negative regulation by host of viral transcription / negative regulation of megakaryocyte differentiation / protein localization to CENP-A containing chromatin / Replacement of protamines by nucleosomes in the male pronucleus / CENP-A containing nucleosome / positive regulation of T-helper 17 cell lineage commitment / Packaging Of Telomere Ends / Recognition and association of DNA glycosylase with site containing an affected purine / Cleavage of the damaged purine / Deposition of new CENPA-containing nucleosomes at the centromere / Recognition and association of DNA glycosylase with site containing an affected pyrimidine / Cleavage of the damaged pyrimidine / Inhibition of DNA recombination at telomere / positive regulation of G2/M transition of mitotic cell cycle / Meiotic synapsis / telomere organization / histone reader activity / RNA Polymerase I Promoter Opening / Assembly of the ORC complex at the origin of replication / SUMOylation of chromatin organization proteins / RNA polymerase II CTD heptapeptide repeat kinase activity / DNA methylation / Condensation of Prophase Chromosomes / ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression / SIRT1 negatively regulates rRNA expression / Chromatin modifications during the maternal to zygotic transition (MZT) / HCMV Late Events / PRC2 methylates histones and DNA / condensed nuclear chromosome / Defective pyroptosis / HDACs deacetylate histones / RNA Polymerase I Promoter Escape / positive regulation of transcription elongation by RNA polymerase II / Nonhomologous End-Joining (NHEJ) / Transcriptional regulation by small RNAs / transcription coregulator activity / Formation of the beta-catenin:TCF transactivating complex / lysine-acetylated histone binding / RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function / NoRC negatively regulates rRNA expression / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / B-WICH complex positively regulates rRNA expression / G2/M DNA damage checkpoint / HDMs demethylate histones / DNA Damage/Telomere Stress Induced Senescence / PKMTs methylate histone lysines / Meiotic recombination / RMTs methylate histone arginines / Pre-NOTCH Transcription and Translation / Activation of anterior HOX genes in hindbrain development during early embryogenesis / HCMV Early Events / Transcriptional regulation of granulopoiesis / structural constituent of chromatin / nucleosome / nucleosome assembly / p53 binding / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / chromatin organization / chromosome / RUNX1 regulates transcription of genes involved in differentiation of HSCs / HATs acetylate histones / Processing of DNA double-strand break ends / regulation of inflammatory response / Senescence-Associated Secretory Phenotype (SASP) / Oxidative Stress Induced Senescence / positive regulation of canonical NF-kappaB signal transduction / Estrogen-dependent gene expression / Potential therapeutics for SARS / chromosome, telomeric region / transcription coactivator activity / transcription cis-regulatory region binding / chromatin remodeling / protein heterodimerization activity / Amyloid fiber formation / 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 / protein-containing complex / DNA binding / RNA binding / extracellular exosome / extracellular region / nucleoplasm / membrane / 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 / Histone H4, conserved site / Histone H4 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 / Histone H4, conserved site / Histone H4 signature. / Histone H4 / Histone H4 / TATA box binding protein associated factor / TATA box binding protein associated factor (TAF), histone-like fold domain / CENP-T/Histone H4, histone fold / Centromere kinetochore component CENP-T histone fold / Bromodomain-like / Histone Acetyltransferase; Chain A / Histone-fold / Bromodomain, conserved site / Bromodomain signature. / Bromodomain / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
FORMIC ACID / Bromodomain-containing protein 4 / Histone H4
Similarity search - Component
Biological speciesHomo sapiens (human)
homo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.91 Å
AuthorsFilippakopoulos, P. / Picaud, S. / Keates, T. / Ugochukwu, E. / von Delft, F. / Arrowsmith, C.H. / Edwards, A.M. / Weigelt, J. / Bountra, C. / Knapp, S. / Structural Genomics Consortium (SGC)
CitationJournal: Cell(Cambridge,Mass.) / Year: 2012
Title: Histone recognition and large-scale structural analysis of the human bromodomain family.
Authors: Filippakopoulos, P. / Picaud, S. / Mangos, M. / Keates, T. / Lambert, J.P. / Barsyte-Lovejoy, D. / Felletar, I. / Volkmer, R. / Muller, S. / Pawson, T. / Gingras, A.C. / Arrowsmith, C.H. / Knapp, S.
History
DepositionNov 30, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 25, 2012Provider: repository / Type: Initial release
Revision 1.1Apr 11, 2012Group: Database references
Revision 1.2Jan 31, 2018Group: Source and taxonomy / Structure summary / Category: audit_author / pdbx_entity_src_syn
Item: _audit_author.name / _pdbx_entity_src_syn.ncbi_taxonomy_id / _pdbx_entity_src_syn.organism_scientific
Revision 1.3Sep 13, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.4Dec 6, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)16,6278
Polymers16,3812
Non-polymers2466
Water1,78399
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1950 Å2
ΔGint-19 kcal/mol
Surface area7520 Å2
MethodPISA
Unit cell
Length a, b, c (Å)43.940, 52.380, 57.620
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
DetailsMonomer

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Components

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Protein / Protein/peptide , 2 types, 2 molecules AB

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


Mass: 15099.380 Da / Num. of mol.: 1 / Fragment: unp residues 44-168
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRD4, HUNK1 / Plasmid: pNIC28-Bsa4 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)-R3 / References: UniProt: O60885
#2: Protein/peptide diacetylated histone 4 peptide / Peptide (H4K12acK16ac)


Mass: 1281.511 Da / Num. of mol.: 1 / Source method: obtained synthetically
Details: Human Histone 4 peptide (Uniprot: P62805) residues 11-21 acetylated on K12 and K16
Source: (synth.) homo sapiens (human) / References: UniProt: P62805*PLUS

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Non-polymers , 4 types, 105 molecules

#3: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-FMT / FORMIC ACID


Mass: 46.025 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: CH2O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 99 / 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: 2.02 Å3/Da / Density meas: 39.23 Mg/m3 / Density % sol: 39.23 %
Crystal growTemperature: 278 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 0.35M NaFortmate 20% PEG 3350 10% EtGly, pH 7.5, VAPOR DIFFUSION, SITTING DROP, temperature 278K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.52 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Dec 6, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.52 Å / Relative weight: 1
ReflectionRedundancy: 4.4 % / Av σ(I) over netI: 4.8 / Number: 47477 / Rsym value: 0.112 / D res high: 1.91 Å / D res low: 22.497 Å / Num. obs: 10804 / % possible obs: 99.9
Diffraction reflection shell
Highest resolution (Å)Lowest resolution (Å)% possible obs (%)IDRmerge(I) obsRsym valueRedundancy
6.0422.598.210.0720.0723.9
4.276.0410010.0720.0724.4
3.494.2710010.0720.0724.4
3.023.4910010.0860.0864.5
2.73.0210010.1080.1084.5
2.472.710010.1540.1544.5
2.282.4710010.2070.2074.5
2.142.2810010.2670.2674.5
2.012.1499.910.3980.3984.4
1.912.0110010.6170.6174.2
ReflectionResolution: 1.91→24.09 Å / Num. all: 10815 / Num. obs: 10804 / % possible obs: 99.9 % / Redundancy: 4.4 % / Biso Wilson estimate: 26.6 Å2 / Rmerge(I) obs: 0.112 / Rsym value: 0.112 / Net I/σ(I): 8.1
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRsym value% possible all
1.91-2.014.20.6171.2640215380.617100
2.01-2.144.40.3981.9650814660.39899.9
2.14-2.284.50.2672.8614413800.267100
2.28-2.474.50.2073.6565412690.207100
2.47-2.74.50.1544.7540812070.154100
2.7-3.024.50.1086.5486710850.108100
3.02-3.494.50.0867.343459670.086100
3.49-4.274.40.0728.237378400.072100
4.27-6.044.40.0727.928766590.072100
6.04-22.4973.90.0727.115363930.07298.2

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Phasing

PhasingMethod: molecular replacement
Phasing MRRfactor: 53.45 / Model details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation2.5 Å22.5 Å
Translation2.5 Å22.5 Å

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Processing

Software
NameVersionClassificationNB
SCALA3.3.16data scaling
PHASER2.1.4phasing
REFMACrefinement
PDB_EXTRACT3.1data extraction
CrystalCleardata collection
MOSFLMdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: Ensemble of 2OSS, 2OUO, 2GRC, 2OO1, 3DAI, 3D7C

2oss

2ouo

2grc

2oo1

3dai

3d7c


Resolution: 1.91→24.09 Å / Cor.coef. Fo:Fc: 0.963 / Cor.coef. Fo:Fc free: 0.944 / WRfactor Rfree: 0.216 / WRfactor Rwork: 0.1627 / Occupancy max: 1 / Occupancy min: 0.5 / FOM work R set: 0.8728 / SU B: 6.294 / SU ML: 0.098 / SU R Cruickshank DPI: 0.1569 / SU Rfree: 0.1476 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.157 / ESU R Free: 0.148 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES: WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2187 517 4.8 %RANDOM
Rwork0.1672 ---
all0.1697 10780 --
obs0.1697 10766 99.87 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 120.77 Å2 / Biso mean: 27.8702 Å2 / Biso min: 11.66 Å2
Baniso -1Baniso -2Baniso -3
1--0.82 Å20 Å20 Å2
2--1.06 Å20 Å2
3----0.24 Å2
Refinement stepCycle: LAST / Resolution: 1.91→24.09 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1101 0 15 99 1215
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.021165
X-RAY DIFFRACTIONr_bond_other_d0.0010.02817
X-RAY DIFFRACTIONr_angle_refined_deg1.4711.9921562
X-RAY DIFFRACTIONr_angle_other_deg0.95132006
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9595132
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.09625.63655
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.96915202
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.329154
X-RAY DIFFRACTIONr_chiral_restr0.0880.2168
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0211238
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02216
LS refinement shellResolution: 1.91→1.959 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.437 30 -
Rwork0.352 656 -
all-686 -
obs--100 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.1386-0.3307-0.41150.33150.12160.8215-0.1162-0.0146-0.22360.05920.02160.05970.0987-0.00430.09460.0701-0.00770.0190.02470.01840.060237.95932.575710.6343
20.5216-0.0637-0.22010.32360.48330.86710.0016-0.0677-0.0260.0599-0.02660.02720.07370.04610.0250.0767-0.00830.00570.0548-0.00470.048238.484739.783413.6362
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A42 - 90
2X-RAY DIFFRACTION2A91 - 168

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