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- PDB-4x2i: Discovery of benzotriazolo diazepines as orally-active inhibitors... -

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Basic information

Entry
Database: PDB / ID: 4x2i
TitleDiscovery of benzotriazolo diazepines as orally-active inhibitors of BET bromodomains: Crystal structure of BRD4 with CPI-13
ComponentsBromodomain-containing protein 4BRD4
KeywordsSIGNALING PROTEIN / BET / CPI-13
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-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-3X0 / FORMIC ACID / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.2 Å
AuthorsBellon, S.F. / Jayaram, H. / Poy, 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
DepositionNov 26, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 11, 2015Provider: repository / Type: Initial release
Revision 1.1Mar 30, 2016Group: Database references
Revision 1.2Feb 28, 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,2393
Polymers14,8681
Non-polymers3712
Water3,297183
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)33.905, 48.181, 78.314
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 14868.111 Da / Num. of mol.: 1 / Fragment: Bromo 1 domain (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-FMT / FORMIC ACID / Formic acid


Mass: 46.025 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: CH2O2
#3: Chemical ChemComp-3X0 / (4R)-6-(4-chlorophenyl)-1,4-dimethyl-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepine


Mass: 324.807 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H17ClN4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 183 / 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: 2.16 Å3/Da / Density % sol: 43.04 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: BRD4-BD1 protein at 1mM, 2.682 M Formate, 10% Glycerol, 0.1 M Tris-HCL pH 8.5

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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: Jan 23, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.2→50 Å / Num. obs: 39985 / % possible obs: 96.2 % / Redundancy: 3 % / Rmerge(I) obs: 0.078 / Net I/σ(I): 17.99
Reflection shellResolution: 1.2→1.24 Å / Rmerge(I) obs: 0.563 / Mean I/σ(I) obs: 2.29

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Processing

Software
NameVersionClassification
REFMAC5.8.0069refinement
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.2→41.04 Å / Cor.coef. Fo:Fc: 0.981 / Cor.coef. Fo:Fc free: 0.968 / SU B: 1.99 / SU ML: 0.038 / Cross valid method: THROUGHOUT / ESU R: 0.037 / ESU R Free: 0.042 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.18729 2004 5 %RANDOM
Rwork0.13813 ---
obs0.14065 37915 96.6 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 22.15 Å2
Baniso -1Baniso -2Baniso -3
1-2.7 Å20 Å20 Å2
2---1.04 Å20 Å2
3----1.66 Å2
Refinement stepCycle: LAST / Resolution: 1.2→41.04 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1046 0 26 183 1255
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0230.021131
X-RAY DIFFRACTIONr_bond_other_d0.0020.021070
X-RAY DIFFRACTIONr_angle_refined_deg2.0611.9921547
X-RAY DIFFRACTIONr_angle_other_deg1.0363.0052474
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.5665131
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.02425.92654
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.25715196
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.829153
X-RAY DIFFRACTIONr_chiral_restr0.1330.2163
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.0211281
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02260
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it3.1041.865515
X-RAY DIFFRACTIONr_mcbond_other3.1021.866516
X-RAY DIFFRACTIONr_mcangle_it3.8742.8646
X-RAY DIFFRACTIONr_mcangle_other3.8722.806647
X-RAY DIFFRACTIONr_scbond_it3.2582.14616
X-RAY DIFFRACTIONr_scbond_other3.2552.139617
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other4.0623.085901
X-RAY DIFFRACTIONr_long_range_B_refined5.13217.081493
X-RAY DIFFRACTIONr_long_range_B_other5.13117.0811494
X-RAY DIFFRACTIONr_rigid_bond_restr5.85532201
X-RAY DIFFRACTIONr_sphericity_free28.368550
X-RAY DIFFRACTIONr_sphericity_bonded11.18852299
LS refinement shellResolution: 1.196→1.227 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.274 124 -
Rwork0.229 2246 -
obs--78.06 %

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