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- PDB-4z1s: Crystal structure of the first bromodomain of human BRD4 with ben... -

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Basic information

Entry
Database: PDB / ID: 4z1s
TitleCrystal structure of the first bromodomain of human BRD4 with benzotriazolo-diazepine scaffold
ComponentsBromodomain-containing protein 4BRD4
KeywordsSIGNALING PROTEIN / 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 / transcription coregulator activity ...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 / transcription coregulator activity / positive regulation of transcription elongation by RNA polymerase II / 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-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-559 / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.06 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

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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)30,5704
Polymers29,7362
Non-polymers8342
Water5,549308
1
A: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,2852
Polymers14,8681
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)15,2852
Polymers14,8681
Non-polymers4171
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)30.376, 39.508, 57.358
Angle α, β, γ (deg.)82.600, 75.430, 90.000
Int Tables number1
Space group name H-MP1

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Components

#1: Protein Bromodomain-containing protein 4 / BRD4 / Protein HUNK1


Mass: 14868.111 Da / Num. of mol.: 2 / Fragment: UNP Residues 42-166
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-559 / 5-[(4S)-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 / Water


Mass: 18.015 Da / Num. of mol.: 308 / 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: 2.18 Å3/Da / Density % sol: 43.64 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / Details: 0.2 M potassium sodium tartrate and 20% PEG 3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 0.9795 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Jan 16, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.06→50 Å / Num. obs: 105981 / % possible obs: 91.4 % / Redundancy: 2.1 % / Rsym value: 0.055 / Net I/σ(I): 14.6
Reflection shellResolution: 1.06→1.1 Å / Redundancy: 1.7 % / Mean I/σ(I) obs: 2.2 / Num. unique all: 9046 / Rsym value: 0.34 / % possible all: 77.9

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Processing

Software
NameVersionClassification
REFMAC5.8.0069refinement
PDB_EXTRACT3.15data extraction
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: Internal model of BRD4-BD1

Resolution: 1.06→50 Å / Cor.coef. Fo:Fc: 0.959 / Cor.coef. Fo:Fc free: 0.943 / SU B: 1.551 / SU ML: 0.034 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.037 / ESU R Free: 0.038 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2196 5291 5 %RANDOM
Rwork0.1854 ---
obs0.1871 100690 91.27 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 67.13 Å2 / Biso mean: 14.553 Å2 / Biso min: 7.66 Å2
Baniso -1Baniso -2Baniso -3
1-0.52 Å2-0.28 Å2-0.89 Å2
2---1.26 Å20.46 Å2
3---0.34 Å2
Refinement stepCycle: final / Resolution: 1.06→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2085 0 60 308 2453
Biso mean--12.35 22.76 -
Num. residues----251
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0280.022267
X-RAY DIFFRACTIONr_bond_other_d0.0030.022156
X-RAY DIFFRACTIONr_angle_refined_deg2.3472.0053099
X-RAY DIFFRACTIONr_angle_other_deg1.0683.0064983
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4865260
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.33325.769104
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.75515397
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.177156
X-RAY DIFFRACTIONr_chiral_restr0.1410.2323
X-RAY DIFFRACTIONr_gen_planes_refined0.0140.0212554
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02518
X-RAY DIFFRACTIONr_mcbond_it1.3910.771031
X-RAY DIFFRACTIONr_mcbond_other1.3780.7691030
X-RAY DIFFRACTIONr_mcangle_it1.6281.1631294
X-RAY DIFFRACTIONr_rigid_bond_restr6.92434423
X-RAY DIFFRACTIONr_sphericity_free21.485544
X-RAY DIFFRACTIONr_sphericity_bonded8.20354614
LS refinement shellResolution: 1.06→1.088 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.286 331 -
Rwork0.26 6097 -
all-6428 -
obs--74.53 %
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)
10.7559-0.0021-0.2070.2872-0.11340.62970.0408-0.0367-0.0150.0055-0.02080.0148-0.0322-0.0002-0.02010.0186-0.00050.01650.0658-0.00790.0203-32.0511-50.155147.252
20.70650.0964-0.12410.24610.00460.53690.03440.03660.0275-0.0056-0.0211-0.0156-0.0226-0.0092-0.01340.02110.01020.02070.0701-0.00020.0227-36.1317-30.631172.4728
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A41 - 166
2X-RAY DIFFRACTION2B41 - 165

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