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- PDB-8fvk: First bromodomain of BRD4 liganded with CCS-1477 -

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Basic information

Entry
Database: PDB / ID: 8fvk
TitleFirst bromodomain of BRD4 liganded with CCS-1477
ComponentsBromodomain-containing protein 4
KeywordsTRANSCRIPTION/INHIBITOR / bromodomain / small molecule ligand / complex / TRANSCRIPTION / TRANSCRIPTION-INHIBITOR complex
Function / homology
Function and homology information


RNA polymerase II C-terminal domain binding / P-TEFb complex binding / negative regulation of DNA damage checkpoint / histone H4 reader activity / host-mediated suppression of viral transcription / positive regulation of G2/M transition of mitotic cell cycle / positive regulation of T-helper 17 cell lineage commitment / : / RNA polymerase II CTD heptapeptide repeat kinase activity / condensed nuclear chromosome ...RNA polymerase II C-terminal domain binding / P-TEFb complex binding / negative regulation of DNA damage checkpoint / histone H4 reader activity / host-mediated suppression of viral transcription / positive regulation of G2/M transition of mitotic cell cycle / positive regulation of T-helper 17 cell lineage commitment / : / RNA polymerase II CTD heptapeptide repeat kinase activity / condensed nuclear chromosome / transcription coregulator activity / positive regulation of transcription elongation by RNA polymerase II / p53 binding / chromosome / regulation of inflammatory response / histone binding / Potential therapeutics for SARS / transcription coactivator activity / positive regulation of canonical NF-kappaB signal transduction / transcription cis-regulatory region binding / chromatin remodeling / protein serine/threonine kinase activity / DNA damage response / chromatin binding / regulation of transcription by RNA polymerase II / chromatin / 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 / Brdt, bromodomain, repeat I / Brdt, bromodomain, repeat II / NET domain superfamily / NET domain profile. / : / NET domain / Bromodomain extra-terminal - transcription regulation / Bromodomain, conserved site ...Bromodomain protein 4, C-terminal / C-terminal domain of bromodomain protein 4 / Brdt, bromodomain, repeat I / Brdt, bromodomain, repeat II / NET domain superfamily / NET domain profile. / : / NET domain / Bromodomain extra-terminal - transcription regulation / Bromodomain, conserved site / Bromodomain signature. / Bromodomain / bromo domain / Bromodomain / Bromodomain (BrD) profile. / Bromodomain-like superfamily
Similarity search - Domain/homology
Chem-JHL / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.53 Å
AuthorsSchonbrunn, E. / Bikowitz, M.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Commun / Year: 2024
Title: Group 3 medulloblastoma transcriptional networks collapse under domain specific EP300/CBP inhibition.
Authors: Shendy, N.A.M. / Bikowitz, M. / Sigua, L.H. / Zhang, Y. / Mercier, A. / Khashana, Y. / Nance, S. / Liu, Q. / Delahunty, I.M. / Robinson, S. / Goel, V. / Rees, M.G. / Ronan, M.A. / Wang, T. / ...Authors: Shendy, N.A.M. / Bikowitz, M. / Sigua, L.H. / Zhang, Y. / Mercier, A. / Khashana, Y. / Nance, S. / Liu, Q. / Delahunty, I.M. / Robinson, S. / Goel, V. / Rees, M.G. / Ronan, M.A. / Wang, T. / Kocak, M. / Roth, J.A. / Wang, Y. / Freeman, B.B. / Orr, B.A. / Abraham, B.J. / Roussel, M.F. / Schonbrunn, E. / Qi, J. / Durbin, A.D.
History
DepositionJan 19, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 7, 2024Provider: repository / Type: Initial release
Revision 1.1Jun 5, 2024Group: 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.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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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)31,5168
Polymers30,1992
Non-polymers1,3176
Water6,702372
1
A: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,7584
Polymers15,0991
Non-polymers6593
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,7584
Polymers15,0991
Non-polymers6593
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)42.000, 54.810, 117.830
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.: 2 / Fragment: bromodomain 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) / References: UniProt: O60885
#2: Chemical ChemComp-JHL / (6S)-1-[3,4-bis(fluoranyl)phenyl]-6-[5-(3,5-dimethyl-1,2-oxazol-4-yl)-1-(4-methoxycyclohexyl)benzimidazol-2-yl]piperidin-2-one / CCS1477 / Inobrodib


Mass: 534.597 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C30H32F2N4O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


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


Mass: 18.015 Da / Num. of mol.: 372 / 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: 2.25 Å3/Da / Density % sol: 45.22 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 0.2M Ammonium sulfate, 0.1M Tris pH8.5, 25% w/v Polyethylene glycol 3350

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Data collection

DiffractionMean temperature: 93 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-BM / Wavelength: 0.97 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Feb 20, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 1.53→34.2 Å / Num. obs: 41819 / % possible obs: 99.7 % / Redundancy: 6.9 % / Biso Wilson estimate: 20.9 Å2 / CC1/2: 0.999 / Rrim(I) all: 0.06 / Net I/σ(I): 21.5
Reflection shellResolution: 1.53→34.2 Å / Redundancy: 4.7 % / Mean I/σ(I) obs: 3.2 / Num. unique obs: 2997 / CC1/2: 0.9 / Rrim(I) all: 0.503 / % possible all: 97.4

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Processing

Software
NameVersionClassification
PHENIX1.19_4092refinement
XDSMar 15, 2019data reduction
XSCALEMar 15, 2019data scaling
PHENIX1.19_4092phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.53→34.2 Å / SU ML: 0.12 / Cross valid method: THROUGHOUT / σ(F): 1.37 / Phase error: 18.6 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1894 1099 2.63 %
Rwork0.1608 --
obs0.1615 41797 99.69 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.53→34.2 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2102 0 94 372 2568
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0092307
X-RAY DIFFRACTIONf_angle_d1.1073154
X-RAY DIFFRACTIONf_dihedral_angle_d7.588302
X-RAY DIFFRACTIONf_chiral_restr0.056330
X-RAY DIFFRACTIONf_plane_restr0.008401
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.53-1.60.22371330.18954934X-RAY DIFFRACTION98
1.6-1.680.22951360.17825042X-RAY DIFFRACTION100
1.68-1.790.21631360.17995005X-RAY DIFFRACTION100
1.79-1.930.22051360.16555048X-RAY DIFFRACTION100
1.93-2.120.19481370.15795063X-RAY DIFFRACTION100
2.12-2.430.20511370.1515077X-RAY DIFFRACTION100
2.43-3.060.17651390.15885157X-RAY DIFFRACTION100
3.06-34.20.16471450.15515372X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: 20.496 Å / Origin y: -15.1096 Å / Origin z: -12.8705 Å
111213212223313233
T0.0937 Å20.0088 Å2-0.0097 Å2-0.1166 Å20.0005 Å2--0.0976 Å2
L0.092 °20.0043 °2-0.0676 °2-0.539 °2-0.0595 °2--0.3299 °2
S-0.0077 Å °-0.0189 Å °-0.0042 Å °0.0226 Å °0.0134 Å °-0.0325 Å °-0.0049 Å °0.0231 Å °-0.0031 Å °
Refinement TLS groupSelection details: all

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