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- PDB-7mce: CRYSTAL STRUCTURE OF THE FIRST BROMODOMAIN OF HUMAN BRD4 IN COMPL... -

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Basic information

Entry
Database: PDB / ID: 7mce
TitleCRYSTAL STRUCTURE OF THE FIRST BROMODOMAIN OF HUMAN BRD4 IN COMPLEX WITH 2-{(7P)-7-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-8-fluoro-5-[(S)-(oxan-4-yl)(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-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 / 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
Chem-YWY / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.76 Å
AuthorsSheriff, S.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2021
Title: Development of BET inhibitors as potential treatments for cancer: A new carboline chemotype.
Authors: Hill, M.D. / Quesnelle, C. / Tokarski, J. / Fang, H. / Fanslau, C. / Haarhoff, Z. / Kramer, M. / Madari, S. / Wiebesiek, A. / Morrison, J. / Simmermacher-Mayer, J. / Sinz, M. / Westhouse, R. ...Authors: Hill, M.D. / Quesnelle, C. / Tokarski, J. / Fang, H. / Fanslau, C. / Haarhoff, Z. / Kramer, M. / Madari, S. / Wiebesiek, A. / Morrison, J. / Simmermacher-Mayer, J. / Sinz, M. / Westhouse, R. / Xie, C. / Zhao, J. / Huang, L. / Sheriff, S. / Yan, C. / Marsilio, F. / Everlof, G. / Zvyaga, T. / Lee, F. / Gavai, A.V. / Degnan, A.P.
History
DepositionApr 2, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 29, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 6, 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 / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)15,7212
Polymers15,2071
Non-polymers5141
Water61334
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)42.500, 42.500, 124.900
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number152
Space group name H-MP3121

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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 BL21(DE3) (bacteria) / References: UniProt: O60885
#2: Chemical ChemComp-YWY / 2-{(7P)-7-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-8-fluoro-5-[(S)-(oxan-4-yl)(phenyl)methyl]-5H-pyrido[3,2-b]indol-3-yl}propan-2-ol


Mass: 513.606 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H32FN5O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 34 / 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: 2.14 Å3/Da / Density % sol: 42.56 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 5.6 / Details: 60% Tacsimate, pH 7.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 0.98 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: May 16, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 1.76→50 Å / Num. obs: 13707 / % possible obs: 99.7 % / Observed criterion σ(I): 0 / Redundancy: 10 % / Biso Wilson estimate: 35.46 Å2 / Rsym value: 0.092 / Net I/σ(I): 19.1
Reflection shellResolution: 1.76→1.82 Å / Redundancy: 10.1 % / Mean I/σ(I) obs: 3 / Num. unique obs: 1314 / Rsym value: 0.824 / % possible all: 99.8

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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: 1.76→35.31 Å / Cor.coef. Fo:Fc: 0.9297 / Cor.coef. Fo:Fc free: 0.9043 / SU R Cruickshank DPI: 0.149 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.151 / SU Rfree Blow DPI: 0.145 / SU Rfree Cruickshank DPI: 0.144
RfactorNum. reflection% reflectionSelection details
Rfree0.2882 987 7.25 %RANDOM
Rwork0.2431 ---
obs0.2461 13609 99.77 %-
Displacement parametersBiso max: 124.79 Å2 / Biso mean: 42.78 Å2 / Biso min: 25.21 Å2
Baniso -1Baniso -2Baniso -3
1--6.632 Å20 Å20 Å2
2---6.632 Å20 Å2
3---13.2639 Å2
Refine analyzeLuzzati coordinate error obs: 0.352 Å
Refinement stepCycle: final / Resolution: 1.76→35.31 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1029 0 38 34 1101
Biso mean--32.97 41.19 -
Num. residues----126
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d373SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes30HARMONIC2
X-RAY DIFFRACTIONt_gen_planes190HARMONIC5
X-RAY DIFFRACTIONt_it1134HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion140SEMIHARMONIC5
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_contact1321SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d1134HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg1579HARMONIC21.02
X-RAY DIFFRACTIONt_omega_torsion2.57
X-RAY DIFFRACTIONt_other_torsion20.67
LS refinement shellResolution: 1.76→1.9 Å / Total num. of bins used: 7
RfactorNum. reflection% reflection
Rfree0.3152 224 8.25 %
Rwork0.2958 2491 -
all0.2973 2715 -
obs--99.77 %

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