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- PDB-5ad2: Bivalent binding to BET bromodomains -

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Basic information

Entry
Database: PDB / ID: 5ad2
TitleBivalent binding to BET bromodomains
ComponentsBROMODOMAIN-CONTAINING PROTEIN 4
KeywordsTRANSCRIPTION
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-ETU / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.01 Å
AuthorsWaring, M.J. / Chen, H. / Rabow, A.A. / Walker, G. / Bobby, R. / Boiko, S. / Bradbury, R.H. / Callis, R. / Dale, I. / Daniels, D. ...Waring, M.J. / Chen, H. / Rabow, A.A. / Walker, G. / Bobby, R. / Boiko, S. / Bradbury, R.H. / Callis, R. / Dale, I. / Daniels, D. / Flavell, L. / Holdgate, G. / Jowitt, T.A. / Kikhney, A. / McAlister, M. / Ogg, D. / Patel, J. / Petteruti, P. / Robb, G.R. / Robers, M. / Stratton, N. / Svergun, D.I. / Wang, W. / Whittaker, D.
CitationJournal: Nat.Chem.Biol. / Year: 2016
Title: Potent and Selective Bivalent Inhibitors of Bet Bromodomains
Authors: Waring, M.J. / Chen, H. / Rabow, A.A. / Walker, G. / Bobby, R. / Boiko, S. / Bradbury, R.H. / Callis, R. / Clark, E. / Dale, I. / Daniels, D.L. / Dulak, A. / Flavell, L. / Holdgate, G. / ...Authors: Waring, M.J. / Chen, H. / Rabow, A.A. / Walker, G. / Bobby, R. / Boiko, S. / Bradbury, R.H. / Callis, R. / Clark, E. / Dale, I. / Daniels, D.L. / Dulak, A. / Flavell, L. / Holdgate, G. / Jowitt, T.A. / Kikhney, A. / Mcalister, M. / Ogg, D. / Patel, J. / Petteruti, P. / Robb, G.R. / Robers, M.B. / Saif, S. / Stratton, N. / Svergun, D.I. / Wang, W. / Whittaker, D. / Wilson, D.M. / Yao, Y.
History
DepositionAug 19, 2015Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 28, 2016Provider: repository / Type: Initial release
Revision 1.1Oct 26, 2016Group: Database references
Revision 1.2Nov 9, 2016Group: Database references
Revision 1.3Nov 30, 2016Group: Database references
Revision 1.4Jan 10, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)30,6833
Polymers30,1992
Non-polymers4841
Water4,630257
1
A: BROMODOMAIN-CONTAINING PROTEIN 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,5832
Polymers15,0991
Non-polymers4841
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: BROMODOMAIN-CONTAINING PROTEIN 4


Theoretical massNumber of molelcules
Total (without water)15,0991
Polymers15,0991
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)41.620, 59.620, 106.770
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 / PROTEIN HUNK1 / BRD4


Mass: 15099.380 Da / Num. of mol.: 2 / Fragment: BROMODOMAIN 1, RESIDUES 44-168
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: O60885
#2: Chemical ChemComp-ETU / (3R)-4-(2-{4-[1-(3-chloro[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-4-piperidinyl]phenoxy}ethyl)-1,3-dimethyl-2-piperazinone


Mass: 483.994 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H30ClN7O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 257 / 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: 43.92 % / Description: NONE
Crystal growDetails: NACL 0.2M, PEG 3350 5.9%W/V, EG 10%V/V, HEPES 0.1M PH 7.4

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E+ SUPERBRIGHT / Wavelength: 1.5418
DetectorType: RIGAKU CCD / Detector: CCD / Date: Apr 3, 2013 / Details: OSMICS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.01→41.62 Å / Num. obs: 17201 / % possible obs: 93.8 % / Observed criterion σ(I): 1.5 / Redundancy: 3.3 % / Biso Wilson estimate: 21.46 Å2 / Rmerge(I) obs: 0.1 / Net I/σ(I): 9.8
Reflection shellResolution: 2.01→2.15 Å / Redundancy: 2 % / Rmerge(I) obs: 0.34 / Mean I/σ(I) obs: 2.6 / % possible all: 71.1

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
MOSFLMdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2OSS

2oss


Resolution: 2.01→34.13 Å / Cor.coef. Fo:Fc: 0.9324 / Cor.coef. Fo:Fc free: 0.8932 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.249 / SU Rfree Blow DPI: 0.193
RfactorNum. reflection% reflectionSelection details
Rfree0.2363 867 5.06 %RANDOM
Rwork0.1795 ---
obs0.1823 17144 93.5 %-
Displacement parametersBiso mean: 24.27 Å2
Baniso -1Baniso -2Baniso -3
1--2.4104 Å20 Å20 Å2
2--4.0367 Å20 Å2
3----1.6262 Å2
Refine analyzeLuzzati coordinate error obs: 0.223 Å
Refinement stepCycle: LAST / Resolution: 2.01→34.13 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2118 0 34 257 2409
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.014363HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.977904HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d960SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes71HARMONIC2
X-RAY DIFFRACTIONt_gen_planes581HARMONIC5
X-RAY DIFFRACTIONt_it4363HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.21
X-RAY DIFFRACTIONt_other_torsion16.01
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion286SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact4806SEMIHARMONIC4
LS refinement shellResolution: 2.01→2.13 Å / Total num. of bins used: 9
RfactorNum. reflection% reflection
Rfree0.2523 108 5.47 %
Rwork0.1909 1865 -
all0.194 1973 -
obs--68.13 %

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