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- PDB-6q3y: Crystal structure of the first bromodomain of human BRD4 in compl... -

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Basic information

Entry
Database: PDB / ID: 6q3y
TitleCrystal structure of the first bromodomain of human BRD4 in complex with the inhibitor 16i
ComponentsBromodomain-containing protein 4
KeywordsGENE REGULATION / BRD4(BD1) / inhibitor / complex / Structural Genomics / Structural Genomics Consortium / SGC
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-like ...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-like / Histone Acetyltransferase; Chain A / Bromodomain, conserved site / Bromodomain signature. / Bromodomain / bromo domain / Bromodomain / Bromodomain (BrD) profile. / Bromodomain-like superfamily / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-HG5 / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.2 Å
AuthorsHeidenreich, D. / Watts, E. / Arrowsmith, C.H. / Bountra, C. / Edwards, A.M. / Knapp, S. / Hoelder, S. / Structural Genomics Consortium (SGC)
CitationJournal: J.Med.Chem. / Year: 2019
Title: Designing Dual Inhibitors of Anaplastic Lymphoma Kinase (ALK) and Bromodomain-4 (BRD4) by Tuning Kinase Selectivity.
Authors: Watts, E. / Heidenreich, D. / Tucker, E. / Raab, M. / Strebhardt, K. / Chesler, L. / Knapp, S. / Bellenie, B. / Hoelder, S.
History
DepositionDec 4, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 6, 2019Provider: repository / Type: Initial release
Revision 1.1Mar 27, 2019Group: Data collection / Database references / Category: citation / citation_author / pdbx_database_proc
Item: _citation.journal_abbrev / _citation.journal_id_ISSN ..._citation.journal_abbrev / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Jan 24, 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: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,72512
Polymers30,1992
Non-polymers1,52610
Water5,927329
1
A: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,9247
Polymers15,0991
Non-polymers8256
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,8005
Polymers15,0991
Non-polymers7014
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)30.340, 39.530, 56.030
Angle α, β, γ (deg.)83.93, 75.64, 89.75
Int Tables number1
Space group name H-MP1

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Components

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


Mass: 15099.380 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRD4, HUNK1 / Production host: Escherichia coli (E. coli) / References: UniProt: O60885
#2: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C2H6O2
#3: Chemical ChemComp-HG5 / (7~{R})-2-[[2-ethoxy-4-(1-methylpiperidin-4-yl)phenyl]amino]-7-ethyl-5-methyl-8-(phenylmethyl)-7~{H}-pteridin-6-one


Mass: 514.662 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C30H38N6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 329 / 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: 2.14 Å3/Da / Density % sol: 42.61 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 30% pentaerythritol ethoxylate 15/4, 0.05 ammonium sulfate, 0.1M bis-tris pH6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.2 / Wavelength: 0.9184 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Jul 14, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 1.2→39.3 Å / Num. obs: 65153 / % possible obs: 83 % / Redundancy: 3.7 % / Rmerge(I) obs: 0.055 / Net I/σ(I): 9.6
Reflection shellResolution: 1.2→1.22 Å / Num. unique obs: 3007 / CC1/2: 0.886 / % possible all: 76.9

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Processing

Software
NameVersionClassification
REFMAC5.8.0238refinement
iMOSFLMdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2OSS

2oss


Resolution: 1.2→39.3 Å / Cor.coef. Fo:Fc: 0.979 / Cor.coef. Fo:Fc free: 0.955 / SU B: 1.725 / SU ML: 0.037 / Cross valid method: THROUGHOUT / ESU R: 0.045 / ESU R Free: 0.046 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.17595 1874 2.9 %RANDOM
Rwork0.14174 ---
obs0.14318 63278 83.02 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 15.016 Å2
Baniso -1Baniso -2Baniso -3
1--0.3 Å20.19 Å2-0.38 Å2
2---0.89 Å2-0.17 Å2
3---0.83 Å2
Refinement stepCycle: 1 / Resolution: 1.2→39.3 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2070 0 108 329 2507
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0132319
X-RAY DIFFRACTIONr_bond_other_d0.0030.0172158
X-RAY DIFFRACTIONr_angle_refined_deg1.4991.6673155
X-RAY DIFFRACTIONr_angle_other_deg1.4251.6455051
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8035258
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.94624.69113
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.15315393
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.808157
X-RAY DIFFRACTIONr_chiral_restr0.0910.2290
X-RAY DIFFRACTIONr_gen_planes_refined0.0120.022838
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02439
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_it1.6241.21005
X-RAY DIFFRACTIONr_mcbond_other1.5735.3941003
X-RAY DIFFRACTIONr_mcangle_it1.8871.8011252
X-RAY DIFFRACTIONr_mcangle_other1.91126.2291253
X-RAY DIFFRACTIONr_scbond_it2.7881.5971314
X-RAY DIFFRACTIONr_scbond_other2.7871.5991315
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other3.1642.2711898
X-RAY DIFFRACTIONr_long_range_B_refined3.2472673
X-RAY DIFFRACTIONr_long_range_B_other3.2482674
X-RAY DIFFRACTIONr_rigid_bond_restr3.24132169
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.2→1.231 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0 0 -
Rwork0.213 4523 -
obs--77.82 %

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