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

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Basic information

Entry
Database: PDB / ID: 5vbo
TitleCRYSTAL STRUCTURE OF THE FIRST BROMODOMAIN OF HUMAN BRD4 IN COMPLEX WITH LRRK2-IN-1
ComponentsBromodomain-containing protein 4
KeywordsTRANSCRIPTION/INHIBITOR / BROMODOMAIN / CAP / HUNK1 / MCAP / PROTEIN BINDING-INHIBITOR COMPLEX / MITOTIC CHROMOSOME ASSOCIATED PROTEIN / INHIBITOR / TRANSCRIPTION-INHIBITOR COMPLEX
Function / homology
Function and homology information


histone H4K8ac reader activity / histone H3K9ac reader activity / RNA polymerase II C-terminal domain binding / histone H3K27ac reader activity / P-TEFb complex binding / negative regulation of DNA damage checkpoint / histone H4 reader activity / histone H4K5ac reader activity / histone H4K12ac reader activity / host-mediated suppression of viral transcription ...histone H4K8ac reader activity / histone H3K9ac reader activity / RNA polymerase II C-terminal domain binding / histone H3K27ac reader activity / P-TEFb complex binding / negative regulation of DNA damage checkpoint / histone H4 reader activity / histone H4K5ac reader activity / histone H4K12ac reader activity / host-mediated suppression of viral transcription / histone H4K16ac reader activity / 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 / positive regulation of DNA-templated transcription / chromatin / 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-4K4 / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.3 Å
AuthorsZHU, J.-Y. / SCHONBRUNN, E.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health & Human Development (NIH/NICHD)HD076542-01S1 United States
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
DepositionMar 30, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 4, 2018Provider: repository / Type: Initial release
Revision 1.1Dec 11, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.2Nov 17, 2021Group: Database references / Category: citation / citation_author / database_2
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 / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3Oct 4, 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)16,0519
Polymers15,0991
Non-polymers9528
Water2,306128
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration, monomer
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)38.810, 50.900, 57.830
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: 15099.380 Da / Num. of mol.: 1 / Fragment: UNP RESIDUES 44-168
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRD4, HUNK1 / Plasmid: PNIC28-BSA4 / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3)-R3 / References: UniProt: O60885
#2: Chemical ChemComp-4K4 / 2-[(2-methoxy-4-{[4-(4-methylpiperazin-1-yl)piperidin-1-yl]carbonyl}phenyl)amino]-5,11-dimethyl-5,11-dihydro-6H-pyrimido[4,5-b][1,4]benzodiazepin-6-one


Mass: 570.685 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H38N8O3
#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


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


Mass: 18.015 Da / Num. of mol.: 128 / 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: 1.89 Å3/Da / Density % sol: 34.97 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 12.5 MG/ML BRD4, 55MM HEPES PH 7.5, 15% Jeffamine ED-2001 pH 7.0, 10% DMSO, 1 MM LRRK2-IN-1

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Feb 17, 2016
RadiationMonochromator: ROSENBAUM-ROCK DOUBLE-CRYSTAL si(220) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.3→30.862 Å / Num. obs: 28353 / % possible obs: 98.2 % / Observed criterion σ(I): -3 / Redundancy: 6.913 % / Biso Wilson estimate: 11.73 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.033 / Rrim(I) all: 0.036 / Χ2: 1.017 / Net I/σ(I): 33.16
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rrim(I) all% possible all
1.3-1.334.120.2316.4218740.950.26388.7
1.33-1.377.0690.2069.6620150.9820.22298.4
1.37-1.417.2540.1612.1819440.990.17298.1
1.41-1.457.2660.14114.0119110.990.15297.9
1.45-1.57.2810.10418.1118320.9950.11298.2
1.5-1.557.2680.08821.1917910.9960.09498.5
1.55-1.617.2390.0712517460.9980.07799.3
1.61-1.687.2460.0629.7516830.9980.06499.3
1.68-1.757.2360.05232.8816230.9990.05699
1.75-1.847.2110.04438.2115520.9990.04899.2
1.84-1.947.2080.03843.8714730.9990.04199.1
1.94-2.067.1420.03449.4214100.9990.03699.4
2.06-2.27.0840.03153.8113150.9990.03399.5
2.2-2.376.9830.02856.6512460.9990.0399.8
2.37-2.66.9890.02759.3311530.9990.0399.7
2.6-2.916.9620.02661.2810440.9990.02899.5
2.91-3.366.8340.02562.769310.9990.02799.9
3.36-4.116.7190.02564.398000.9980.027100
4.11-5.816.3970.02763.786380.9980.02999.7
5.81-30.8625.6050.03159.223720.9980.03498.7

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
XSCALEdata scaling
SERGUIdata collection
PHENIX1.9_1692refinement
PDB_EXTRACT3.22data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4O74

4o74


Resolution: 1.3→30.862 Å / SU ML: 0.07 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 16.15
RfactorNum. reflection% reflection
Rfree0.1635 1220 4.3 %
Rwork0.1487 --
obs-28352 98.24 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 82.28 Å2 / Biso mean: 19.6424 Å2 / Biso min: 6.68 Å2
Refinement stepCycle: final / Resolution: 1.3→30.862 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1043 0 132 128 1303
Biso mean--26.15 25.73 -
Num. residues----125
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0091168
X-RAY DIFFRACTIONf_angle_d1.3491584
X-RAY DIFFRACTIONf_chiral_restr0.069160
X-RAY DIFFRACTIONf_plane_restr0.008201
X-RAY DIFFRACTIONf_dihedral_angle_d19.557457
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 9

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.3001-1.35210.19821250.18222769289492
1.3521-1.41370.18161330.16862966309998
1.4137-1.48820.17351340.16292978311298
1.4882-1.58140.18451340.1562981311599
1.5814-1.70350.19551350.14783017315299
1.7035-1.87490.18291370.15093031316899
1.8749-2.14620.15061370.140130643201100
2.1462-2.70370.15471390.139430873226100
2.7037-30.87090.15231460.148132393385100
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)
14.5841-3.65734.4613.1366-3.51134.36160.26310.1809-0.18180.0027-0.0621-0.03570.15340.3051-0.14740.11930.00840.0060.1192-0.00080.14620.0573-11.59787.0028
28.46771.8478-1.41636.4071-1.42478.3517-0.0013-0.0549-0.1119-0.1405-0.0297-0.48150.05090.4620.0420.0983-0.004-0.02950.09390.00750.0803-14.9107-4.7432-5.497
34.2331-0.43024.41230.530.30075.9036-0.14-0.19690.22050.049-0.07780.0264-0.1644-0.24320.24250.0938-0.01220.00650.0992-0.04270.1244-17.2461-2.056414.4719
42.6876-0.0606-0.18884.57691.35561.5133-0.0309-0.1952-0.05720.20760.0809-0.26370.11210.1815-0.03160.0849-0.0033-0.00250.1060.01680.0632-1.1344-15.27815.929
51.6313-1.26371.8042.0368-2.55294.3810.0217-0.04880.0162-0.001-0.0160.00330.0487-0.1136-0.040.05280.00190.01440.0536-0.00940.0666-13.7359-10.32038.3812
67.88566.1128-2.31756.2859-3.02457.6208-0.111-0.9515-0.24930.9088-0.25690.08960.48330.34150.21730.24090.00190.03340.18280.04140.1106-9.338-19.919427.7718
77.41-2.88772.74964.6708-2.8454.2227-0.0465-0.2206-0.06020.15640.17990.30950.0168-0.3431-0.11990.1046-0.03540.04820.1129-0.03020.1152-21.5339-9.872619.0484
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 60 )A52 - 60
3X-RAY DIFFRACTION3chain 'A' and (resid 61 through 83 )A61 - 83
4X-RAY DIFFRACTION4chain 'A' and (resid 84 through 106 )A84 - 106
5X-RAY DIFFRACTION5chain 'A' and (resid 107 through 139 )A107 - 139
6X-RAY DIFFRACTION6chain 'A' and (resid 140 through 144 )A140 - 144
7X-RAY DIFFRACTION7chain 'A' and (resid 145 through 166 )A145 - 166

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