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

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Basic information

Entry
Database: PDB / ID: 5nng
TitleCrystal Structure of the first bromodomain of human BRD4 in complex with an acetylated SRPK1 peptide (K585ac)
Components
  • Bromodomain-containing protein 4
  • VAG(ALY)YS(ALY)EFFY
KeywordsTRANSCRIPTION / Bromodomain / complex / Structural Genomics / Structural Genomics Consortium / SGC
Function / homology
Function and homology information


sperm DNA condensation / regulation of mRNA processing / regulation of mRNA splicing, via spliceosome / Maturation of nucleoprotein / negative regulation of viral genome replication / spliceosomal complex assembly / RNA polymerase II C-terminal domain binding / negative regulation of DNA damage checkpoint / P-TEFb complex binding / negative regulation by host of viral transcription ...sperm DNA condensation / regulation of mRNA processing / regulation of mRNA splicing, via spliceosome / Maturation of nucleoprotein / negative regulation of viral genome replication / spliceosomal complex assembly / 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 viral genome replication / Replacement of protamines by nucleosomes in the male pronucleus / 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 / RNA splicing / condensed nuclear chromosome / chromosome segregation / positive regulation of transcription elongation by RNA polymerase II / transcription coregulator activity / lysine-acetylated histone binding / nuclear matrix / p53 binding / chromosome / regulation of inflammatory response / positive regulation of canonical NF-kappaB signal transduction / Potential therapeutics for SARS / transcription coactivator activity / non-specific serine/threonine protein kinase / transcription cis-regulatory region binding / protein kinase activity / intracellular signal transduction / nuclear speck / chromatin remodeling / protein phosphorylation / innate immune response / protein serine kinase activity / protein serine/threonine kinase activity / DNA damage response / chromatin binding / chromatin / regulation of transcription by RNA polymerase II / positive regulation of DNA-templated transcription / enzyme binding / magnesium ion binding / endoplasmic reticulum / positive regulation of transcription by RNA polymerase II / RNA binding / nucleoplasm / ATP binding / nucleus / plasma membrane / cytoplasm / cytosol
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 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
Bromodomain-containing protein 4 / SRSF protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.2 Å
AuthorsFilippakopoulos, P. / Picaud, S. / Newman, J. / Sorrell, F. / von Delft, F. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C. / Structural Genomics Consortium (SGC)
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: 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
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
B: VAG(ALY)YS(ALY)EFFY
hetero molecules


Theoretical massNumber of molelcules
Total (without water)16,6464
Polymers16,5222
Non-polymers1242
Water3,585199
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: isothermal titration calorimetry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1070 Å2
ΔGint0 kcal/mol
Surface area8740 Å2
MethodPISA
Unit cell
Length a, b, c (Å)37.051, 44.141, 81.746
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 / 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 VAG(ALY)YS(ALY)EFFY


Mass: 1422.580 Da / Num. of mol.: 1 / Source method: obtained synthetically
Details: SRPK1 peptide acetylated at K585 and K588 C-terminal TYR added for UV detection
Source: (synth.) Homo sapiens (human) / References: UniProt: Q96SB4*PLUS
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 199 / 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 % sol: 39.2 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7 / Details: 30% PEG1000 0.1M PCB pH 7.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I02 / Wavelength: 0.97949 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Apr 16, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97949 Å / Relative weight: 1
ReflectionResolution: 1.2→40.87 Å / Num. obs: 42718 / % possible obs: 99 % / Redundancy: 6.3 % / Rmerge(I) obs: 0.051 / Rpim(I) all: 0.022 / Rrim(I) all: 0.022 / Rsym value: 0.051 / Net I/σ(I): 18.2
Reflection shellResolution: 1.2→1.26 Å / Redundancy: 6.3 % / Rmerge(I) obs: 0.518 / Mean I/σ(I) obs: 4.3 / Num. unique all: 6132 / Num. unique obs: 38775 / Rpim(I) all: 0.221 / Rrim(I) all: 0.221 / Rsym value: 0.564 / % possible all: 100

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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: 1.2→40.87 Å / Cor.coef. Fo:Fc: 0.977 / Cor.coef. Fo:Fc free: 0.972 / SU B: 1.075 / SU ML: 0.022 / Cross valid method: THROUGHOUT / ESU R: 0.035 / ESU R Free: 0.036 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.15773 2011 4.7 %RANDOM
Rwork0.12727 ---
obs0.12872 40641 99.87 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 15.284 Å2
Baniso -1Baniso -2Baniso -3
1-0.5 Å20 Å2-0 Å2
2---0.68 Å20 Å2
3---0.19 Å2
Refinement stepCycle: 1 / Resolution: 1.2→40.87 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1161 0 8 199 1368
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.021248
X-RAY DIFFRACTIONr_bond_other_d0.0020.021138
X-RAY DIFFRACTIONr_angle_refined_deg1.5971.9841699
X-RAY DIFFRACTIONr_angle_other_deg1.01132674
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4995144
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.66625.55663
X-RAY DIFFRACTIONr_dihedral_angle_3_deg10.1715213
X-RAY DIFFRACTIONr_dihedral_angle_4_deg25.46154
X-RAY DIFFRACTIONr_chiral_restr0.1160.2179
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0211355
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02237
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_it1.6872.416565
X-RAY DIFFRACTIONr_mcbond_other1.6482.411564
X-RAY DIFFRACTIONr_mcangle_it1.924.545705
X-RAY DIFFRACTIONr_mcangle_other1.9224.55706
X-RAY DIFFRACTIONr_scbond_it3.2373.09683
X-RAY DIFFRACTIONr_scbond_other3.2373.09683
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other3.6615.497992
X-RAY DIFFRACTIONr_long_range_B_refined3.44618.1081520
X-RAY DIFFRACTIONr_long_range_B_other3.27817.461475
X-RAY DIFFRACTIONr_rigid_bond_restr2.33332386
X-RAY DIFFRACTIONr_sphericity_free21.5675119
X-RAY DIFFRACTIONr_sphericity_bonded7.90752430
LS refinement shellResolution: 1.2→1.231 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.201 159 -
Rwork0.175 2938 -
obs--100 %

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