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- PDB-5nne: Crystal Structure of the first bromodomain of human BRD4 in compl... -

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Basic information

Entry
Database: PDB / ID: 5nne
TitleCrystal Structure of the first bromodomain of human BRD4 in complex with a diacetylated TOP2A peptide (K1201ac/K1204ac)
Components
  • Bromodomain-containing protein 4BRD4
  • GKA(ALY)GK(ALY)TQMY
KeywordsTRANSCRIPTION / Bromodomain / complex
Function / homology
Function and homology information


negative regulation of DNA duplex unwinding / positive regulation of single stranded viral RNA replication via double stranded DNA intermediate / sister chromatid segregation / apoptotic chromosome condensation / DNA topoisomerase type II (double strand cut, ATP-hydrolyzing) complex / resolution of meiotic recombination intermediates / female meiotic nuclear division / DNA ligation / embryonic cleavage / Transcription of E2F targets under negative control by DREAM complex ...negative regulation of DNA duplex unwinding / positive regulation of single stranded viral RNA replication via double stranded DNA intermediate / sister chromatid segregation / apoptotic chromosome condensation / DNA topoisomerase type II (double strand cut, ATP-hydrolyzing) complex / resolution of meiotic recombination intermediates / female meiotic nuclear division / DNA ligation / embryonic cleavage / Transcription of E2F targets under negative control by DREAM complex / DNA topoisomerase type II (double strand cut, ATP-hydrolyzing) activity / DNA binding, bending / DNA topoisomerase (ATP-hydrolysing) / SUMOylation of DNA replication proteins / DNA topological change / RNA polymerase II C-terminal domain binding / chromosome, centromeric region / negative regulation of DNA damage checkpoint / P-TEFb complex binding / negative regulation by host of viral transcription / ATP-dependent activity, acting on DNA / hematopoietic progenitor cell differentiation / condensed chromosome / positive regulation of G2/M transition of mitotic cell cycle / histone reader activity / RNA polymerase II CTD heptapeptide repeat kinase activity / protein kinase C binding / ubiquitin binding / condensed nuclear chromosome / male germ cell nucleus / chromosome segregation / positive regulation of transcription elongation by RNA polymerase II / transcription coregulator activity / lysine-acetylated histone binding / regulation of circadian rhythm / rhythmic process / 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 / ribonucleoprotein complex / positive regulation of apoptotic process / protein heterodimerization activity / DNA damage response / chromatin binding / nucleolus / regulation of transcription by RNA polymerase II / positive regulation of DNA-templated transcription / magnesium ion binding / enzyme binding / protein homodimerization activity / positive regulation of transcription by RNA polymerase II / protein-containing complex / DNA binding / RNA binding / nucleoplasm / ATP binding / nucleus / cytoplasm
Similarity search - Function
DTHCT / DTHCT (NUC029) region / DNA topoisomerase 2, TOPRIM domain / DNA topoisomerase II, eukaryotic-type / C-terminal associated domain of TOPRIM / C-terminal associated domain of TOPRIM / Topoisomerase (Topo) IIA-type catalytic domain profile. / DNA topoisomerase, type IIA, alpha-helical domain superfamily / DNA topoisomerase, type IIA, domain A / DNA topoisomerase, type IIA, domain A, alpha-beta ...DTHCT / DTHCT (NUC029) region / DNA topoisomerase 2, TOPRIM domain / DNA topoisomerase II, eukaryotic-type / C-terminal associated domain of TOPRIM / C-terminal associated domain of TOPRIM / Topoisomerase (Topo) IIA-type catalytic domain profile. / DNA topoisomerase, type IIA, alpha-helical domain superfamily / DNA topoisomerase, type IIA, domain A / DNA topoisomerase, type IIA, domain A, alpha-beta / DNA gyrase/topoisomerase IV, subunit A / DNA Topoisomerase IV / DNA topoisomerase, type IIA, subunit B, domain 2 / DNA gyrase B / DNA topoisomerase, type IIA / DNA topoisomerase, type IIA, conserved site / DNA topoisomerase II signature. / TopoisomeraseII / DNA topoisomerase, type IIA, subunit B, C-terminal / Toprim domain / DNA topoisomerase, type IIA-like domain superfamily / Toprim domain profile. / TOPRIM domain / 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 / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase / Histidine kinase/HSP90-like ATPase / Histidine kinase/HSP90-like ATPase superfamily / Bromodomain-like / Histone Acetyltransferase; Chain A / Bromodomain, conserved site / Bromodomain signature. / Bromodomain / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily / Ribosomal protein S5 domain 2-type fold, subgroup / Ribosomal protein S5 domain 2-type fold / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
Bromodomain-containing protein 4 / DNA topoisomerase 2-alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.15 Å
AuthorsFilippakopoulos, P. / Picaud, S. / Krojer, T. / von Delft, F. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Wellcome Trust095751/Z/11/Z United Kingdom
CitationJournal: Mol. Cell / Year: 2019
Title: Interactome Rewiring Following Pharmacological Targeting of BET Bromodomains.
Authors: Lambert, J.P. / Picaud, S. / Fujisawa, T. / Hou, H. / Savitsky, P. / Uuskula-Reimand, L. / Gupta, G.D. / Abdouni, H. / Lin, Z.Y. / Tucholska, M. / Knight, J.D.R. / Gonzalez-Badillo, B. / St- ...Authors: Lambert, J.P. / Picaud, S. / Fujisawa, T. / Hou, H. / Savitsky, P. / Uuskula-Reimand, L. / Gupta, G.D. / Abdouni, H. / Lin, Z.Y. / Tucholska, M. / Knight, J.D.R. / Gonzalez-Badillo, B. / St-Denis, N. / Newman, J.A. / Stucki, M. / Pelletier, L. / Bandeira, N. / Wilson, M.D. / Filippakopoulos, P. / Gingras, A.C.
History
DepositionApr 8, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 16, 2018Provider: repository / Type: Initial release
Revision 1.1Nov 28, 2018Group: Data collection / Database references / Category: citation / citation_author / Item: _citation.title / _citation_author.name
Revision 1.2Dec 26, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.3Feb 20, 2019Group: Data collection / Database references
Category: citation / database_PDB_rev ...citation / database_PDB_rev / database_PDB_rev_record / pdbx_database_proc
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year
Revision 1.4Jan 17, 2024Group: 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

Downloads & links

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Assembly

Deposited unit
A: Bromodomain-containing protein 4
C: GKA(ALY)GK(ALY)TQMY
hetero molecules


Theoretical massNumber of molelcules
Total (without water)16,4873
Polymers16,4252
Non-polymers621
Water2,558142
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: isothermal titration calorimetry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1310 Å2
ΔGint-6 kcal/mol
Surface area8050 Å2
MethodPISA
Unit cell
Length a, b, c (Å)41.347, 53.032, 58.193
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 15099.380 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRD4, HUNK1 / Plasmid: pNIC28-Bsa4 / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): R3 / References: UniProt: O60885
#2: Protein/peptide GKA(ALY)GK(ALY)TQMY


Mass: 1325.576 Da / Num. of mol.: 1 / Source method: obtained synthetically
Details: TOP2A peptide acetylated at K1201 and K1204. Additional C-terminal TYR added for UV detection
Source: (synth.) Homo sapiens (human) / References: UniProt: P11388*PLUS
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 142 / 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: 1.94 Å3/Da / Density % sol: 36.67 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7.5 / Details: 20% PEG3350 10% ethylene glycol 0.2M sodium iodide

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.97625 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Dec 15, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97625 Å / Relative weight: 1
ReflectionResolution: 1.15→29.1 Å / Num. obs: 46081 / % possible obs: 99 % / Redundancy: 6.9 % / Rmerge(I) obs: 0.037 / Rpim(I) all: 0.015 / Rrim(I) all: 0.015 / Rsym value: 0.037 / Net I/σ(I): 22.5
Reflection shellResolution: 1.61→1.7 Å / Redundancy: 4.9 % / Rmerge(I) obs: 0.741 / Mean I/σ(I) obs: 2 / Num. unique all: 2595 / Rsym value: 0.741 / % possible all: 98.2

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Processing

Software
NameVersionClassification
REFMAC5.8.0158refinement
XDSdata reduction
SCALAdata scaling
PHASERphasing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2OSS

2oss


Resolution: 1.15→29.1 Å / Cor.coef. Fo:Fc: 0.975 / Cor.coef. Fo:Fc free: 0.97 / SU B: 0.893 / SU ML: 0.019 / Cross valid method: THROUGHOUT / ESU R: 0.032 / ESU R Free: 0.033 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.16414 1918 4.2 %RANDOM
Rwork0.13892 ---
obs0.13996 44103 99.67 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 18.087 Å2
Baniso -1Baniso -2Baniso -3
1-0.04 Å2-0 Å2-0 Å2
2---0.56 Å20 Å2
3---0.51 Å2
Refinement stepCycle: 1 / Resolution: 1.15→29.1 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1116 0 4 142 1262
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.021186
X-RAY DIFFRACTIONr_bond_other_d0.0020.021114
X-RAY DIFFRACTIONr_angle_refined_deg1.6881.9871615
X-RAY DIFFRACTIONr_angle_other_deg1.05832621
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.0295145
X-RAY DIFFRACTIONr_dihedral_angle_2_deg372655
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.13515214
X-RAY DIFFRACTIONr_dihedral_angle_4_deg24.866153
X-RAY DIFFRACTIONr_chiral_restr0.1050.2174
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0211281
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02214
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_it2.2493.149550
X-RAY DIFFRACTIONr_mcbond_other2.1773.136549
X-RAY DIFFRACTIONr_mcangle_it2.6325.896687
X-RAY DIFFRACTIONr_mcangle_other2.6625.909688
X-RAY DIFFRACTIONr_scbond_it2.7683.642636
X-RAY DIFFRACTIONr_scbond_other2.7663.647637
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other3.2516.554922
X-RAY DIFFRACTIONr_long_range_B_refined3.41422.2011399
X-RAY DIFFRACTIONr_long_range_B_other3.23121.7471373
X-RAY DIFFRACTIONr_rigid_bond_restr2.32832300
X-RAY DIFFRACTIONr_sphericity_free23.4593
X-RAY DIFFRACTIONr_sphericity_bonded8.8352315
LS refinement shellResolution: 1.15→1.18 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.226 132 -
Rwork0.212 3171 -
obs--97.98 %

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