4X2I

Discovery of benzotriazolo diazepines as orally-active inhibitors of BET bromodomains: Crystal structure of BRD4 with CPI-13


X-RAY DIFFRACTION

Crystallization

Crystalization Experiments
IDMethodpHTemperatureDetails
1VAPOR DIFFUSION, SITTING DROP8.5277BRD4-BD1 protein at 1mM, 2.682 M Formate, 10% Glycerol, 0.1 M Tris-HCL pH 8.5
Crystal Properties
Matthews coefficientSolvent content
2.1643.04

Crystal Data

Unit Cell
Length ( Å )Angle ( ˚ )
a = 33.905α = 90
b = 48.181β = 90
c = 78.314γ = 90
Symmetry
Space GroupP 21 21 21

Diffraction

Diffraction Experiment
ID #Crystal IDScattering TypeData Collection TemperatureDetectorDetector TypeDetailsCollection DateMonochromatorProtocol
11x-ray100CCDMARMOSAIC 300 mm CCD2012-01-23MSINGLE WAVELENGTH
Radiation Source
ID #SourceTypeWavelength ListSynchrotron SiteBeamline
1SYNCHROTRONAPS BEAMLINE 22-ID1.00APS22-ID

Data Collection

Overall
ID #Resolution (High)Resolution (Low)Percent Possible (Observed)R Merge I (Observed)Net I Over Average Sigma (I)RedundancyNumber Reflections (All)Number Reflections (Observed)Observed Criterion Sigma (F)Observed Criterion Sigma (I)B (Isotropic) From Wilson Plot
11.25096.20.07817.99339985
Highest Resolution Shell
ID #Resolution (High)Resolution (Low)Percent Possible (All)Percent Possible (Observed)R Merge I (Observed)Mean I Over Sigma (Observed)RedundancyNumber Unique Reflections (All)
11.21.240.5632.29

Refinement

Statistics
Diffraction IDStructure Solution MethodCross Validation methodResolution (High)Resolution (Low)Number Reflections (Observed)Number Reflections (R-Free)Percent Reflections (Observed)R-Factor (Observed)R-WorkR-FreeR-Free Selection DetailsMean Isotropic B
X-RAY DIFFRACTIONMOLECULAR REPLACEMENTTHROUGHOUT1.241.0437915200496.60.140650.138130.18729RANDOM22.15
Temperature Factor Modeling
Anisotropic B[1][1]Anisotropic B[1][2]Anisotropic B[1][3]Anisotropic B[2][2]Anisotropic B[2][3]Anisotropic B[3][3]
2.7-1.04-1.66
RMS Deviations
KeyRefinement Restraint Deviation
r_dihedral_angle_2_deg36.024
r_sphericity_free28.368
r_dihedral_angle_4_deg13.829
r_dihedral_angle_3_deg13.257
r_sphericity_bonded11.188
r_rigid_bond_restr5.855
r_dihedral_angle_1_deg5.566
r_long_range_B_refined5.132
r_long_range_B_other5.131
r_scangle_other4.062
RMS Deviations
KeyRefinement Restraint Deviation
r_dihedral_angle_2_deg36.024
r_sphericity_free28.368
r_dihedral_angle_4_deg13.829
r_dihedral_angle_3_deg13.257
r_sphericity_bonded11.188
r_rigid_bond_restr5.855
r_dihedral_angle_1_deg5.566
r_long_range_B_refined5.132
r_long_range_B_other5.131
r_scangle_other4.062
r_mcangle_it3.874
r_mcangle_other3.872
r_scbond_it3.258
r_scbond_other3.255
r_mcbond_it3.104
r_mcbond_other3.102
r_angle_refined_deg2.061
r_angle_other_deg1.036
r_chiral_restr0.133
r_bond_refined_d0.023
r_gen_planes_refined0.011
r_bond_other_d0.002
r_gen_planes_other0.002
r_nbd_refined
r_nbd_other
r_nbtor_refined
r_nbtor_other
r_xyhbond_nbd_refined
r_xyhbond_nbd_other
r_metal_ion_refined
r_metal_ion_other
r_symmetry_vdw_refined
r_symmetry_vdw_other
r_symmetry_hbond_refined
r_symmetry_hbond_other
r_symmetry_metal_ion_refined
r_symmetry_metal_ion_other
r_scangle_it
Non-Hydrogen Atoms Used in Refinement
Non-Hydrogen AtomsNumber
Protein Atoms1046
Nucleic Acid Atoms
Solvent Atoms183
Heterogen Atoms26

Software

Software
Software NamePurpose
REFMACrefinement
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing