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- PDB-4z1q: Crystal structure of the first bromodomain of human BRD4 bound to... -

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Basic information

Entry
Database: PDB / ID: 4z1q
TitleCrystal structure of the first bromodomain of human BRD4 bound to benzotriazolo-diazepine scaffold
ComponentsBromodomain-containing protein 4
KeywordsTRANSCRIPTION / bromodomain
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-558 / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.399 Å
AuthorsSetser, J.W. / Poy, F. / Tang, Y. / Bellon, S.F.
CitationJournal: Acs Med.Chem.Lett. / Year: 2016
Title: Discovery of Benzotriazolo[4,3-d][1,4]diazepines as Orally Active Inhibitors of BET Bromodomains.
Authors: Taylor, A.M. / Vaswani, R.G. / Gehling, V.S. / Hewitt, M.C. / Leblanc, Y. / Audia, J.E. / Bellon, S. / Cummings, R.T. / Cote, A. / Harmange, J.C. / Jayaram, H. / Joshi, S. / Lora, J.M. / ...Authors: Taylor, A.M. / Vaswani, R.G. / Gehling, V.S. / Hewitt, M.C. / Leblanc, Y. / Audia, J.E. / Bellon, S. / Cummings, R.T. / Cote, A. / Harmange, J.C. / Jayaram, H. / Joshi, S. / Lora, J.M. / Mertz, J.A. / Neiss, A. / Pardo, E. / Nasveschuk, C.G. / Poy, F. / Sandy, P. / Setser, J.W. / Sims, R.J. / Tang, Y. / Albrecht, B.K.
History
DepositionMar 27, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 8, 2015Provider: repository / Type: Initial release
Revision 1.1Mar 30, 2016Group: Database references
Revision 1.2Mar 6, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_oper_list
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation

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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)30,8284
Polymers29,9942
Non-polymers8342
Water3,765209
1
A: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,4142
Polymers14,9971
Non-polymers4171
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,4142
Polymers14,9971
Non-polymers4171
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)30.293, 39.501, 57.230
Angle α, β, γ (deg.)83.070, 75.350, 89.850
Int Tables number1
Space group name H-MP1

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Components

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


Mass: 14997.226 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-558 / 5-[(4R)-6-(4-chlorophenyl)-1,4-dimethyl-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepin-8-yl]pyridin-2-amine


Mass: 416.906 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H21ClN6
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 209 / 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: 2.19 Å3/Da / Density % sol: 43.88 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 0.2 M sodium chloride, 0.1 M Bis-Tris pH 6.5, and 25% polyethylene glycol (PEG) 3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: RAYONIX MX300HS / Detector: CCD / Date: Feb 23, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.399→50 Å / Num. obs: 42635 / % possible obs: 84.9 % / Redundancy: 1.8 % / Rmerge(I) obs: 0.071 / Rpim(I) all: 0.071 / Rrim(I) all: 0.1 / Χ2: 1.044 / Net I/av σ(I): 10.029 / Net I/σ(I): 10.9 / Num. measured all: 75841
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.399-1.451.10.42827490.6170.4280.6061.07654.6
1.45-1.511.20.40531400.6460.4050.5731.06462
1.51-1.581.40.40337370.6270.4030.5691.09375.3
1.58-1.661.70.42845400.60.4280.6061.07590
1.66-1.7620.32747660.7380.3270.4631.04195.1
1.76-1.920.19848210.8830.1980.281.06895.7
1.9-2.0920.12348060.9490.1230.1731.01895.9
2.09-2.391.90.07848060.9780.0780.111.00795.7
2.39-3.0220.05446530.9890.0540.0771.01992.2
3.02-5020.03546170.9930.0350.051.06892.2

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Processing

Software
NameVersionClassification
HKL-2000data collection
SCALEPACKdata scaling
REFMAC5.8.0069refinement
PDB_EXTRACT3.15data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: Internal model

Resolution: 1.399→50 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.922 / SU B: 3.152 / SU ML: 0.065 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.086 / ESU R Free: 0.09 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2423 2084 4.9 %RANDOM
Rwork0.2034 ---
obs0.2053 40551 84.74 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 54.8 Å2 / Biso mean: 16.187 Å2 / Biso min: 6.46 Å2
Baniso -1Baniso -2Baniso -3
1-0.01 Å2-0.18 Å20.05 Å2
2---0.67 Å2-0.22 Å2
3---0.54 Å2
Refinement stepCycle: final / Resolution: 1.399→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2091 0 60 209 2360
Biso mean--15.18 22.38 -
Num. residues----251
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0220.022318
X-RAY DIFFRACTIONr_bond_other_d0.0030.022194
X-RAY DIFFRACTIONr_angle_refined_deg2.0642.0053182
X-RAY DIFFRACTIONr_angle_other_deg0.9873.0065074
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.3255271
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.98125.926108
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.91415404
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.55156
X-RAY DIFFRACTIONr_chiral_restr0.1250.2333
X-RAY DIFFRACTIONr_gen_planes_refined0.0120.0212652
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02532
X-RAY DIFFRACTIONr_mcbond_it1.0540.9441057
X-RAY DIFFRACTIONr_mcbond_other1.0540.9411056
X-RAY DIFFRACTIONr_mcangle_it1.6531.4041337
LS refinement shellResolution: 1.399→1.435 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.271 85 -
Rwork0.238 1880 -
all-1965 -
obs--52.25 %
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)
11.0528-0.1776-0.27150.1982-0.06620.61870.0373-0.0318-0.03260.0051-0.02160.0175-0.02640.0348-0.01570.00520.01040.00460.06890.02050.0098-23.5735-52.3493148.0565
21.20110.1697-0.43310.3223-0.08880.80430.06590.0290.07140.0183-0.0207-0.0078-0.048-0.0513-0.04520.00780.01690.00910.07450.02830.0142-27.5975-32.7761173.2828
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A43 - 166
2X-RAY DIFFRACTION2B41 - 167

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