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- PDB-5ad3: Bivalent binding to BET bromodomains -

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Basic information

Entry
Database: PDB / ID: 5ad3
TitleBivalent binding to BET bromodomains
ComponentsBROMODOMAIN-CONTAINING PROTEIN 4BRD4
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 / 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-K6K / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.49 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)30,7293
Polymers30,1992
Non-polymers5311
Water4,270237
1
A: 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
2
B: BROMODOMAIN-CONTAINING PROTEIN 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,6302
Polymers15,0991
Non-polymers5311
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)109.640, 41.826, 59.591
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 / 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-K6K / 3-methoxy-N-[2-[4-[1-(3-methoxy-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-4-piperidyl]phenoxy]ethyl]-N-methyl-[1,2,4]triazolo[4,3-b]pyridazin-6-amine


Mass: 530.582 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H30N10O3
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 237 / 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: 2.26 Å3/Da / Density % sol: 45.63 % / Description: NONE
Crystal growDetails: PEG 4K 20%W/V, (NH4)2HPO4 0.2M

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 20, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.49→52.36 Å / Num. obs: 45639 / % possible obs: 100 % / Observed criterion σ(I): 0 / Redundancy: 6.9 % / Biso Wilson estimate: 20.24 Å2 / Rmerge(I) obs: 0.1 / Net I/σ(I): 11.2
Reflection shellResolution: 1.49→1.57 Å / Redundancy: 7.1 % / Rmerge(I) obs: 0.66 / Mean I/σ(I) obs: 2.3 / % possible all: 100

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Processing

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

2oss


Resolution: 1.49→29.8 Å / Cor.coef. Fo:Fc: 0.8694 / Cor.coef. Fo:Fc free: 0.8332 / SU R Cruickshank DPI: 0.119 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.11 / SU Rfree Blow DPI: 0.11 / SU Rfree Cruickshank DPI: 0.106
RfactorNum. reflection% reflectionSelection details
Rfree0.3081 2278 5.04 %RANDOM
Rwork0.269 ---
obs0.271 45179 99.09 %-
Displacement parametersBiso mean: 24.91 Å2
Baniso -1Baniso -2Baniso -3
1--4.3443 Å20 Å20 Å2
2---5.7196 Å20 Å2
3---10.0639 Å2
Refine analyzeLuzzati coordinate error obs: 0.329 Å
Refinement stepCycle: LAST / Resolution: 1.49→29.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2118 0 39 237 2394
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.014340HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.997876HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d943SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes72HARMONIC2
X-RAY DIFFRACTIONt_gen_planes577HARMONIC5
X-RAY DIFFRACTIONt_it4340HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.94
X-RAY DIFFRACTIONt_other_torsion16.88
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion283SEMIHARMONIC5
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_contact4637SEMIHARMONIC4
LS refinement shellResolution: 1.49→1.53 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.3617 149 4.56 %
Rwork0.3754 3122 -
all0.3748 3271 -
obs--99.37 %
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)
11.50110.0570.22990.7616-0.00650.87440.07370.06820.01330.00450.0329-0.0795-0.0096-0.019-0.1066-0.2240.014-0.0768-0.172-0.04290.1328122.505-32.55222.0687
21.04-0.0821-0.35790.4345-0.09261.06320.00360.0559-0.0864-0.02870.0025-0.10670.0771-0.0109-0.006-0.2010.00450.0553-0.17150.00550.1024152.551-49.7282.6483

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