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- PDB-7k6h: Crystal structure of the first bromodomain (BD1) of human BRD4 bo... -

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Basic information

Entry
Database: PDB / ID: 7k6h
TitleCrystal structure of the first bromodomain (BD1) of human BRD4 bound to XMD8-92
ComponentsBromodomain-containing protein 4BRD4
KeywordsGENE REGULATION / BET / ERK5 / dual BRD-kinase inhibitor
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-4WG / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.5 Å
AuthorsKarim, M.R. / Zhu, J.Y. / Schonbrunn, E.
CitationJournal: J.Med.Chem. / Year: 2021
Title: Differential BET Bromodomain Inhibition by Dihydropteridinone and Pyrimidodiazepinone Kinase Inhibitors.
Authors: Karim, R.M. / Bikowitz, M.J. / Chan, A. / Zhu, J.Y. / Grassie, D. / Becker, A. / Berndt, N. / Gunawan, S. / Lawrence, N.J. / Schonbrunn, E.
History
DepositionSep 20, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 22, 2021Provider: repository / Type: Initial release
Revision 1.1Nov 17, 2021Group: 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 1.2Nov 24, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Oct 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

Downloads & links

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Assembly

Deposited unit
A: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,5742
Polymers15,0991
Non-polymers4751
Water2,216123
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area7790 Å2
MethodPISA
Unit cell
Length a, b, c (Å)41.820, 52.030, 57.270
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 / BRD4 / 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 / Production host: Escherichia coli (E. coli) / References: UniProt: O60885
#2: Chemical ChemComp-4WG / 2-{[2-ethoxy-4-(4-hydroxypiperidin-1-yl)phenyl]amino}-5,11-dimethyl-5,11-dihydro-6H-pyrimido[4,5-b][1,4]benzodiazepin-6-one


Mass: 474.555 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H30N6O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 123 / 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: 2.06 Å3/Da / Density % sol: 40.38 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop
Details: 0.2 M Ammonium acetate, 0.1 M Sodium citrate tribasic dihydrate pH 5.6, 30% w/v Polyethylene glycol 4,000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Apr 5, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.5→28.635 Å / Num. obs: 20618 / % possible obs: 99.9 % / Redundancy: 6.999 % / Biso Wilson estimate: 16.68 Å2 / CC1/2: 0.991 / Rmerge(I) obs: 0.107 / Rrim(I) all: 0.116 / Χ2: 0.985 / Net I/σ(I): 18.6 / Num. measured all: 144304
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsCC1/2Rrim(I) all% possible all
1.5-1.547.0590.09615.6310695151515150.9920.104100
1.54-1.587.0480.09116.0110184144514450.9910.098100
1.58-1.637.0480.0916.6510001142014190.9920.09799.9
1.63-1.687.080.08617.569898139813980.9920.093100
1.68-1.737.0810.08317.929397132713270.9930.089100
1.73-1.797.0620.08418.29216130513050.9920.091100
1.79-1.867.0970.08418.948935125912590.9930.091100
1.86-1.947.0990.08319.368576120812080.990.089100
1.94-2.027.1380.0819.758259115711570.9930.086100
2.02-2.127.0760.08219.857826110711060.9930.08999.9
2.12-2.247.0850.08420.17588107210710.990.09199.9
2.24-2.377.0670.09519.997166101510140.9860.10399.9
2.37-2.547.040.120.2166889509500.9850.109100
2.54-2.746.9490.11320.0762829049040.9860.122100
2.74-36.8830.11720.0256308208180.9850.12799.8
3-3.356.8410.11720.0150907447440.9840.126100
3.35-3.876.7520.11319.9445176696690.9820.122100
3.87-4.746.7160.11119.8739295855850.9830.12100
4.74-6.716.4630.11519.4229154524510.9840.12599.8
6.71-28.6355.5380.10917.7715122772730.9780.11998.6

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Processing

Software
NameVersionClassification
PHENIX1.12-2829_2829refinement
XSCALEdata scaling
PDB_EXTRACT3.25data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7K6G

7k6g


Resolution: 1.5→28.635 Å / SU ML: 0.11 / Cross valid method: THROUGHOUT / σ(F): 1.4 / Phase error: 18.8 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1903 1031 5 %
Rwork0.1649 19582 -
obs0.1662 20613 99.96 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 145.86 Å2 / Biso mean: 29.6633 Å2 / Biso min: 10.2 Å2
Refinement stepCycle: final / Resolution: 1.5→28.635 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1059 0 65 123 1247
Biso mean--28.92 38.14 -
Num. residues----127
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0061171
X-RAY DIFFRACTIONf_angle_d0.8711603
X-RAY DIFFRACTIONf_chiral_restr0.041165
X-RAY DIFFRACTIONf_plane_restr0.005207
X-RAY DIFFRACTIONf_dihedral_angle_d17.673724
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork
1.5-1.57910.22761450.1772754
1.5791-1.6780.20751450.16822757
1.678-1.80760.22191440.17522745
1.8076-1.98950.18561470.16642777
1.9895-2.27720.17411460.15392786
2.2772-2.86860.17641480.17262812
2.8686-28.6350.19281560.16122951
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
12.24051.61561.58962.18092.03481.9913-0.00480.5526-0.0935-0.2304-0.14710.2847-0.4002-0.4260.10960.29660.09860.01450.22680.05930.2016-18.316111.4003-23.1907
25.8846-2.36095.26491.5221-2.35394.8910.03520.50230.0192-0.1974-0.107-0.04260.19530.47840.07890.1242-0.01290.01790.127-0.00340.18311.54610.8417-25.6351
33.8078-1.4612-5.71743.64613.12778.8529-0.3551-0.7315-0.44320.21610.12270.14810.71090.42970.15840.16550.03050.02430.15310.02970.2-3.1740.908-10.5939
48.114-4.13262.93112.4574-0.92532.0505-0.1518-0.8584-0.19460.51930.30080.1342-0.084-0.2911-0.11640.1830.00140.03250.17290.02780.1511-10.47285.7535-4.6808
53.9873-4.7277-0.05365.9364-0.11471.9118-0.3573-0.7324-0.34540.61730.56750.8309-0.2902-0.93-0.12450.18930.09870.06220.35480.02580.2341-21.323413.6465-11.9328
64.5935-3.733-2.77254.22123.55584.66870.06120.11570.0449-0.1922-0.09120.0442-0.2292-0.17840.04230.0987-0.0019-0.01250.09910.01190.1157-9.0419.9969-20.8482
76.7478-6.1001-6.94295.57786.51617.75020.2289-0.01390.2367-0.27630.0618-0.3544-0.27440.1127-0.31430.1191-0.01430.00070.1-0.00280.1664-4.15214.817-15.5127
85.7488-4.4919-5.6755.89724.57127.9265-0.0247-0.38140.18440.07660.2703-0.46410.17180.4647-0.10520.1267-0.0286-0.02250.1184-0.00310.1806-0.301911.001-8.0287
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 42 through 51 )A42 - 51
2X-RAY DIFFRACTION2chain 'A' and (resid 52 through 68 )A52 - 68
3X-RAY DIFFRACTION3chain 'A' and (resid 69 through 76 )A69 - 76
4X-RAY DIFFRACTION4chain 'A' and (resid 77 through 83 )A77 - 83
5X-RAY DIFFRACTION5chain 'A' and (resid 84 through 96 )A84 - 96
6X-RAY DIFFRACTION6chain 'A' and (resid 97 through 121 )A97 - 121
7X-RAY DIFFRACTION7chain 'A' and (resid 122 through 139 )A122 - 139
8X-RAY DIFFRACTION8chain 'A' and (resid 140 through 168 )A140 - 168

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