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

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Basic information

Entry
Database: PDB / ID: 5kdh
TitleCRYSTAL STRUCTURE OF THE FIRST BROMODOMAIN OF HUMAN BRD4 IN COMPLEX WITH A DIHYDROPYRIDOPYRIMIDINE SCAFFOLD INHIBITOR
ComponentsBromodomain-containing protein 4
KeywordsTRANSCRIPTION/INHIBITOR / BROMODOMAIN / CAP / HUNK1 / MCAP / PROTEIN BINDING-INHIBITOR COMPLEX / MITOTIC CHROMOSOME ASSOCIATED PROTEIN / CELL CYCLE / INHIBITOR / TRANSCRIPTION-INHIBITOR COMPLEX
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-like / Histone Acetyltransferase; Chain A ...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-like / Histone Acetyltransferase; Chain A / Bromodomain, conserved site / Bromodomain signature. / Bromodomain / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-6RX / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.5 Å
AuthorsZhu, J.-Y. / Schonbrunn, E.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health & Human Development (NIH/NICHD)5 U01 HD076542 (GIG) United States
National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health & Human Development (NIH/NICHD)HHSN275201300017C (GIG) United States
CitationJournal: J. Med. Chem. / Year: 2017
Title: BET Bromodomain Inhibitors with One-Step Synthesis Discovered from Virtual Screen.
Authors: Ayoub, A.M. / Hawk, L.M.L. / Herzig, R.J. / Jiang, J. / Wisniewski, A.J. / Gee, C.T. / Zhao, P. / Zhu, J.Y. / Berndt, N. / Offei-Addo, N.K. / Scott, T.G. / Qi, J. / Bradner, J.E. / Ward, T.R. ...Authors: Ayoub, A.M. / Hawk, L.M.L. / Herzig, R.J. / Jiang, J. / Wisniewski, A.J. / Gee, C.T. / Zhao, P. / Zhu, J.Y. / Berndt, N. / Offei-Addo, N.K. / Scott, T.G. / Qi, J. / Bradner, J.E. / Ward, T.R. / Schonbrunn, E. / Georg, G.I. / Pomerantz, W.C.K.
History
DepositionJun 8, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 2, 2017Provider: repository / Type: Initial release
Revision 1.1Sep 13, 2017Group: Author supporting evidence / Category: pdbx_audit_support
Revision 1.2Dec 11, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Sep 27, 2023Group: 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,6935
Polymers15,0991
Non-polymers5944
Water1,72996
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)42.120, 48.560, 61.600
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-6RX / (5~{S})-1-ethyl-5-(4-methylphenyl)-8,9-dihydro-5~{H}-furo[3,4]pyrido[3,5-~{b}]pyrimidine-2,4,6-trione


Mass: 339.345 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H17N3O4
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 96 / 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: 2.09 Å3/Da / Density % sol: 41.04 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 12.5 MG/ML BRD4, 5MM HEPES PH 7.5, 50MM SODIUM CHLORIDE, 0.5MM DTT, 50MM TRIS PH8.5, 0.1M AMMONIUM, SULFATE, 12.5% PEG 3,350, 10% DMSO, 1 MM INHIBITOR

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: MARMOSAIC 225 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: 1.5→38.135 Å / Num. obs: 20642 / % possible obs: 99 % / Observed criterion σ(I): -3 / Redundancy: 7.1 % / Biso Wilson estimate: 16.2 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.038 / Net I/σ(I): 27.78
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsDiffraction-ID% possible all
1.5-1.547.30.3545.43198.9
1.54-1.587.30.3076.31197.8
1.58-1.637.30.2428.19197.8
1.63-1.687.30.29.98198.9
1.68-1.737.30.16112.18199.1
1.73-1.797.30.13514.45198.6
1.79-1.867.30.10318.74198.8
1.86-1.947.20.08123.37198.9
1.94-2.027.20.06428.03199.3
2.02-2.127.10.05233.81199.2
2.12-2.2470.04538.79199.5
2.24-2.3770.04141.65199.4
2.37-2.546.90.03544.52199.7
2.54-2.7470.03248.84199.6
2.74-36.80.02852.04199.9
3-3.356.80.02855.7199.6
3.35-3.876.70.02459.01199.9
3.87-4.746.70.02260.97199.8
4.74-6.716.70.02258.72199.8
6.71-1005.60.02954.67198.6

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation1.5 Å38.14 Å
Translation1.5 Å38.14 Å

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Processing

Software
NameVersionClassification
XSCALEdata scaling
PHASER2.5.6phasing
PHENIX1.9_1692refinement
PDB_EXTRACT3.2data extraction
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4O7A

4o7a


Resolution: 1.5→38.135 Å / SU ML: 0.12 / Cross valid method: FREE R-VALUE / σ(F): 1.38 / Phase error: 17.16
RfactorNum. reflection% reflection
Rfree0.184 1033 5 %
Rwork0.158 --
obs-20641 99.02 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 151.13 Å2 / Biso mean: 27.5423 Å2 / Biso min: 8.44 Å2
Refinement stepCycle: final / Resolution: 1.5→38.135 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1062 0 62 96 1220
Biso mean--30.13 29.7 -
Num. residues----127
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0091178
X-RAY DIFFRACTIONf_angle_d1.2691614
X-RAY DIFFRACTIONf_chiral_restr0.052165
X-RAY DIFFRACTIONf_plane_restr0.007210
X-RAY DIFFRACTIONf_dihedral_angle_d13.538455
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 7

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.5001-1.57910.25041440.18352727287198
1.5791-1.67810.17171440.16122736288098
1.6781-1.80770.18131450.15722748289399
1.8077-1.98960.16411460.15342784293099
1.9896-2.27740.17681480.14572798294699
2.2774-2.86920.19441490.16128432992100
2.8692-38.14780.18151570.158929723129100
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)
13.5829-1.42184.32910.8925-1.53665.3511-0.1125-0.0562-0.21150.12970.1808-0.0208-0.0111-0.0693-0.04030.15580.03920.03650.1377-0.00230.159511.9734-7.40441.3021
24.4502-3.36740.12055.30360.23542.74170.144-0.2929-0.31620.2681-0.204-0.9531-0.42960.4566-0.01710.1932-0.0778-0.090.21040.04450.275428.4398-0.0654-2.7629
37.5845-0.78821.92981.4176-1.81824.1821-0.01040.10660.3747-0.09150.1026-0.2098-0.36410.3529-0.05290.1693-0.02690.00970.06380.00770.184920.99353.8926-15.2873
43.9727-0.761-0.21471.8211-1.3651.28480.07860.45630.3317-0.15230.18920.4455-0.1863-0.69670.01470.13910.0282-0.02570.28590.05420.16474.9844-3.28-16.8699
51.93270.37010.53942.1827-0.24334.7408-0.0823-0.04020.02070.00620.0012-0.07880.09210.07140.06430.07780.01450.01590.07460.0170.094316.1046-8.7003-8.5616
62.26-2.1271-1.91043.81321.96351.6290.02561.0158-0.1124-1.6089-0.0274-0.07980.7825-0.95510.11840.54-0.019-0.01390.28650.01780.192712.0998-10.3868-28.1435
75.3528-0.01983.1122.40720.18093.74970.26840.11960.3672-0.0669-0.2815-0.41690.25210.4278-0.01850.1097-0.0120.04470.1860.03590.197426.2632-4.4863-15.6892
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 42 through 60 )A42 - 60
2X-RAY DIFFRACTION2chain 'A' and (resid 61 through 68 )A61 - 68
3X-RAY DIFFRACTION3chain 'A' and (resid 69 through 80 )A69 - 80
4X-RAY DIFFRACTION4chain 'A' and (resid 81 through 96 )A81 - 96
5X-RAY DIFFRACTION5chain 'A' and (resid 97 through 139 )A97 - 139
6X-RAY DIFFRACTION6chain 'A' and (resid 140 through 144 )A140 - 144
7X-RAY DIFFRACTION7chain 'A' and (resid 145 through 168 )A145 - 168

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