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

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Basic information

Entry
Database: PDB / ID: 5nnf
TitleCrystal Structure of the first bromodomain of human BRD4 in complex with an acetylated BAZ1B peptide (K221ac)
Components
  • Bromodomain-containing protein 4BRD4
  • FLPH(ALY)YDVKL
KeywordsTRANSCRIPTION / Bromodomain / complex
Function / homology
Function and homology information


histone H2AXY142 kinase activity / WICH complex / negative regulation of mitotic chromosome condensation / histone kinase activity / B-WICH complex / : / positive regulation of transcription by RNA polymerase III / positive regulation of transcription by RNA polymerase I / RNA polymerase II C-terminal domain binding / negative regulation of DNA damage checkpoint ...histone H2AXY142 kinase activity / WICH complex / negative regulation of mitotic chromosome condensation / histone kinase activity / B-WICH complex / : / positive regulation of transcription by RNA polymerase III / positive regulation of transcription by RNA polymerase I / 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 / pericentric heterochromatin / condensed chromosome / positive regulation of G2/M transition of mitotic cell cycle / histone reader activity / post-translational protein modification / RNA polymerase II CTD heptapeptide repeat kinase activity / condensed nuclear chromosome / positive regulation of transcription elongation by RNA polymerase II / transcription coregulator activity / non-specific protein-tyrosine kinase / lysine-acetylated histone binding / non-membrane spanning protein tyrosine kinase activity / B-WICH complex positively regulates rRNA expression / p53 binding / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / chromosome / histone binding / 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 / phosphorylation / DNA damage response / chromatin binding / nucleolus / regulation of transcription by RNA polymerase II / positive regulation of DNA-templated transcription / enzyme binding / positive regulation of transcription by RNA polymerase II / zinc ion binding / nucleoplasm / ATP binding / nucleus
Similarity search - Function
Tyrosine-protein kinase BAZ1B, bromodomain / : / : / WSTF/Acf1/Cbp146 / ATP-utilising chromatin assembly and remodelling N-terminal / WAC domain profile. / WHIM1 domain / WSTF, HB1, Itc1p, MBD9 motif 1 / DDT domain / WHIM2 domain ...Tyrosine-protein kinase BAZ1B, bromodomain / : / : / WSTF/Acf1/Cbp146 / ATP-utilising chromatin assembly and remodelling N-terminal / WAC domain profile. / WHIM1 domain / WSTF, HB1, Itc1p, MBD9 motif 1 / DDT domain / WHIM2 domain / Williams-Beuren syndrome DDT (WSD), D-TOX E motif / DDT domain profile. / domain in different transcription and chromosome remodeling factors / 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 / Zinc finger, PHD-type, conserved site / PHD-finger / Zinc finger PHD-type signature. / Zinc finger PHD-type profile. / Zinc finger, PHD-finger / Zinc finger, PHD-type / PHD zinc finger / Bromodomain-like / Histone Acetyltransferase; Chain A / Zinc finger, RING-type / Zinc finger, FYVE/PHD-type / Bromodomain, conserved site / Bromodomain signature. / Bromodomain / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily / Zinc finger, RING/FYVE/PHD-type / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
Bromodomain-containing protein 4 / Tyrosine-protein kinase BAZ1B
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
United Kingdom
CitationJournal: Mol Cell / Year: 2019
Title: Interactome Rewiring Following Pharmacological Targeting of BET Bromodomains.
Authors: Jean-Philippe Lambert / Sarah Picaud / Takao Fujisawa / Huayun Hou / Pavel Savitsky / Liis Uusküla-Reimand / Gagan D Gupta / Hala Abdouni / Zhen-Yuan Lin / Monika Tucholska / James D R ...Authors: Jean-Philippe Lambert / Sarah Picaud / Takao Fujisawa / Huayun Hou / Pavel Savitsky / Liis Uusküla-Reimand / Gagan D Gupta / Hala Abdouni / Zhen-Yuan Lin / Monika Tucholska / James D R Knight / Beatriz Gonzalez-Badillo / Nicole St-Denis / Joseph A Newman / Manuel Stucki / Laurence Pelletier / Nuno Bandeira / Michael D Wilson / Panagis Filippakopoulos / Anne-Claude Gingras /
Abstract: Targeting bromodomains (BRDs) of the bromo-and-extra-terminal (BET) family offers opportunities for therapeutic intervention in cancer and other diseases. Here, we profile the interactomes of BRD2, ...Targeting bromodomains (BRDs) of the bromo-and-extra-terminal (BET) family offers opportunities for therapeutic intervention in cancer and other diseases. Here, we profile the interactomes of BRD2, BRD3, BRD4, and BRDT following treatment with the pan-BET BRD inhibitor JQ1, revealing broad rewiring of the interaction landscape, with three distinct classes of behavior for the 603 unique interactors identified. A group of proteins associate in a JQ1-sensitive manner with BET BRDs through canonical and new binding modes, while two classes of extra-terminal (ET)-domain binding motifs mediate acetylation-independent interactions. Last, we identify an unexpected increase in several interactions following JQ1 treatment that define negative functions for BRD3 in the regulation of rRNA synthesis and potentially RNAPII-dependent gene expression that result in decreased cell proliferation. Together, our data highlight the contributions of BET protein modules to their interactomes allowing for a better understanding of pharmacological rewiring in response to JQ1.
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

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Assembly

Deposited unit
A: Bromodomain-containing protein 4
B: FLPH(ALY)YDVKL


Theoretical massNumber of molelcules
Total (without water)16,4032
Polymers16,4032
Non-polymers00
Water3,765209
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: isothermal titration calorimetry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1160 Å2
ΔGint-9 kcal/mol
Surface area7680 Å2
MethodPISA
Unit cell
Length a, b, c (Å)37.439, 43.915, 79.690
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 FLPH(ALY)YDVKL


Mass: 1303.547 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: Q9UIG0*PLUS
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 209 / 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 Å3/Da / Density % sol: 38.4 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 20% PEG3350 10% ethylene glycol 0.1M bis-tris-propane pH 8.5 0.02M sodium/potassium phosphate

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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→29.51 Å / Num. obs: 47482 / % possible obs: 99.1 % / Redundancy: 6.8 % / Rmerge(I) obs: 0.037 / Rpim(I) all: 0.015 / Rrim(I) all: 0.015 / Rsym value: 0.037 / Net I/σ(I): 33.9
Reflection shellResolution: 1.15→1.21 Å / Redundancy: 5.8 % / Rmerge(I) obs: 0.084 / Mean I/σ(I) obs: 15.5 / Num. unique all: 6775 / Rsym value: 0.084 / % possible all: 99.3

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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→29.51 Å / Cor.coef. Fo:Fc: 0.976 / Cor.coef. Fo:Fc free: 0.97 / SU B: 0.638 / SU ML: 0.014 / Cross valid method: THROUGHOUT / ESU R: 0.028 / ESU R Free: 0.029 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.14448 1946 4.1 %RANDOM
Rwork0.11893 ---
obs0.12002 45469 99.85 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 12.17 Å2
Baniso -1Baniso -2Baniso -3
1-0.78 Å20 Å20 Å2
2---0.33 Å20 Å2
3----0.45 Å2
Refinement stepCycle: 1 / Resolution: 1.15→29.51 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1119 0 0 209 1328
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.021192
X-RAY DIFFRACTIONr_bond_other_d0.0020.021100
X-RAY DIFFRACTIONr_angle_refined_deg1.7151.9751630
X-RAY DIFFRACTIONr_angle_other_deg1.08832587
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8465144
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.02625.34558
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.82315213
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.75154
X-RAY DIFFRACTIONr_chiral_restr0.1120.2174
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0211292
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02226
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_it1.1551.945546
X-RAY DIFFRACTIONr_mcbond_other1.1441.932545
X-RAY DIFFRACTIONr_mcangle_it1.4763.638682
X-RAY DIFFRACTIONr_mcangle_other1.4793.649683
X-RAY DIFFRACTIONr_scbond_it1.7212.382646
X-RAY DIFFRACTIONr_scbond_other1.7222.385647
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other2.1174.281943
X-RAY DIFFRACTIONr_long_range_B_refined2.501151484
X-RAY DIFFRACTIONr_long_range_B_other2.18714.0711424
X-RAY DIFFRACTIONr_rigid_bond_restr1.92432292
X-RAY DIFFRACTIONr_sphericity_free19.0175120
X-RAY DIFFRACTIONr_sphericity_bonded6.51352341
LS refinement shellResolution: 1.15→1.18 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.124 122 -
Rwork0.091 3270 -
obs--98.35 %

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