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- PDB-5s9r: CRYSTAL STRUCTURE OF THE FIRST BROMODOMAIN OF HUMAN BRD4 IN COMPL... -

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Basic information

Entry
Database: PDB / ID: 5s9r
TitleCRYSTAL STRUCTURE OF THE FIRST BROMODOMAIN OF HUMAN BRD4 IN COMPLEX WITH BMS-986158, 2-{3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-(oxan-4-yl)(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol
ComponentsBromodomain-containing protein 4
KeywordsCELL CYCLE / BROMODOMAIN-CONTAINING PROTEIN 4 ISOFORM LONG / BRD4 / BROMODOMAIN CONTAINING PROTEIN 4 / CAP / HUNK1 / MCAP / MITOTIC CHROMOSOME ASSOCIATED PROTEIN SGC
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 / 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 / condensed nuclear chromosome / positive regulation of transcription elongation by RNA polymerase II ...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 / positive regulation of G2/M transition of mitotic cell cycle / histone reader activity / RNA polymerase II CTD heptapeptide repeat kinase activity / condensed nuclear chromosome / positive regulation of transcription elongation by RNA polymerase II / transcription coregulator activity / lysine-acetylated histone binding / 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 / 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 / nucleoplasm / 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 / Bromodomain, conserved site / Bromodomain 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 / Bromodomain, conserved site / Bromodomain signature. / Bromodomain / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily
Similarity search - Domain/homology
IODIDE ION / Chem-YWA / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.85 Å
AuthorsSheriff, S.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: J.Med.Chem. / Year: 2021
Title: Discovery and Preclinical Pharmacology of an Oral Bromodomain and Extra-Terminal (BET) Inhibitor Using Scaffold-Hopping and Structure-Guided Drug Design.
Authors: Gavai, A.V. / Norris, D. / Delucca, G. / Tortolani, D. / Tokarski, J.S. / Dodd, D. / O'Malley, D. / Zhao, Y. / Quesnelle, C. / Gill, P. / Vaccaro, W. / Huynh, T. / Ahuja, V. / Han, W.C. / ...Authors: Gavai, A.V. / Norris, D. / Delucca, G. / Tortolani, D. / Tokarski, J.S. / Dodd, D. / O'Malley, D. / Zhao, Y. / Quesnelle, C. / Gill, P. / Vaccaro, W. / Huynh, T. / Ahuja, V. / Han, W.C. / Mussari, C. / Harikrishnan, L. / Kamau, M. / Poss, M. / Sheriff, S. / Yan, C. / Marsilio, F. / Menard, K. / Wen, M.L. / Rampulla, R. / Wu, D.R. / Li, J. / Zhang, H. / Li, P. / Sun, D. / Yip, H. / Traeger, S.C. / Zhang, Y. / Mathur, A. / Zhang, H. / Huang, C. / Yang, Z. / Ranasinghe, A. / Everlof, G. / Raghavan, N. / Tye, C.K. / Wee, S. / Hunt, J.T. / Vite, G. / Westhouse, R. / Lee, F.Y.
History
DepositionApr 1, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 29, 2021Provider: repository / Type: Initial release
Revision 1.1Nov 17, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2May 22, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)16,2087
Polymers15,2071
Non-polymers1,0006
Water66737
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)39.600, 48.500, 58.100
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 15207.499 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRD4, HUNK1 / Plasmid: PET28 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: O60885
#2: Chemical ChemComp-YWA / 2-{3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-(oxan-4-yl)(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol


Mass: 495.615 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H33N5O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-IOD / IODIDE ION


Mass: 126.904 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: I
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


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


Mass: 18.015 Da / Num. of mol.: 37 / 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: 1.83 Å3/Da / Density % sol: 32.95 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.8
Details: 100mM Bis-Tris Propane, pH 7.82, 200mM sodium iodide, 20%(w/v) PEG3350, 10% (v/v) ethylene glycol

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 0.98 / Wavelength: 0.98 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: May 4, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 1.85→50 Å / Num. obs: 10069 / % possible obs: 99.7 % / Observed criterion σ(I): 0 / Redundancy: 5.9 % / Biso Wilson estimate: 23.35 Å2 / Rsym value: 0.102 / Net I/σ(I): 16.2
Reflection shellResolution: 1.85→1.92 Å / Redundancy: 5.8 % / Mean I/σ(I) obs: 3.2 / Rsym value: 0.669 / Rejects: 0 / % possible all: 100

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
BUSTER2.11.5refinement
PDB_EXTRACT3.22data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3MXF

3mxf


Resolution: 1.85→13.54 Å / Cor.coef. Fo:Fc: 0.8952 / Cor.coef. Fo:Fc free: 0.8803 / SU R Cruickshank DPI: 0.175 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.177 / SU Rfree Blow DPI: 0.144 / SU Rfree Cruickshank DPI: 0.143
RfactorNum. reflection% reflectionSelection details
Rfree0.2313 820 8.23 %RANDOM
Rwork0.2077 ---
obs0.2096 9958 99.78 %-
Displacement parametersBiso max: 92.04 Å2 / Biso mean: 23.93 Å2 / Biso min: 8.53 Å2
Baniso -1Baniso -2Baniso -3
1-8.0838 Å20 Å20 Å2
2---14.4991 Å20 Å2
3---6.4153 Å2
Refine analyzeLuzzati coordinate error obs: 0.214 Å
Refinement stepCycle: final / Resolution: 1.85→13.54 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1036 0 48 37 1121
Biso mean--23.78 28.75 -
Num. residues----126
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d379SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes32HARMONIC2
X-RAY DIFFRACTIONt_gen_planes191HARMONIC5
X-RAY DIFFRACTIONt_it1148HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion138SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact1363SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d1148HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg1593HARMONIC20.96
X-RAY DIFFRACTIONt_omega_torsion3.01
X-RAY DIFFRACTIONt_other_torsion17.32
LS refinement shellResolution: 1.85→2.07 Å / Total num. of bins used: 5
RfactorNum. reflection% reflection
Rfree0.2514 232 8.32 %
Rwork0.1819 2557 -
all0.1878 2789 -
obs--99.78 %

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