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- PDB-7khl: BRD4-BD1 Compound6 (methyl 4-(3,5-difluoropyridin-2-yl)-10-methyl... -

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Basic information

Entry
Database: PDB / ID: 7khl
TitleBRD4-BD1 Compound6 (methyl 4-(3,5-difluoropyridin-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-6-carboxylate)
ComponentsBromodomain-containing protein 4BRD4
KeywordsCELL CYCLE / SBDD
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, conserved site / Bromodomain signature. ...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, conserved site / Bromodomain signature. / Bromodomain / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily
Similarity search - Domain/homology
Chem-WEM / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.286 Å
AuthorsMurray, J.M.
CitationJournal: J.Med.Chem. / Year: 2021
Title: Antibody-Mediated Delivery of Chimeric BRD4 Degraders. Part 2: Improvement of In Vitro Antiproliferation Activity and In Vivo Antitumor Efficacy.
Authors: Dragovich, P.S. / Pillow, T.H. / Blake, R.A. / Sadowsky, J.D. / Adaligil, E. / Adhikari, P. / Chen, J. / Corr, N. / Dela Cruz-Chuh, J. / Del Rosario, G. / Fullerton, A. / Hartman, S.J. / ...Authors: Dragovich, P.S. / Pillow, T.H. / Blake, R.A. / Sadowsky, J.D. / Adaligil, E. / Adhikari, P. / Chen, J. / Corr, N. / Dela Cruz-Chuh, J. / Del Rosario, G. / Fullerton, A. / Hartman, S.J. / Jiang, F. / Kaufman, S. / Kleinheinz, T. / Kozak, K.R. / Liu, L. / Lu, Y. / Mulvihill, M.M. / Murray, J.M. / O'Donohue, A. / Rowntree, R.K. / Sawyer, W.S. / Staben, L.R. / Wai, J. / Wang, J. / Wei, B. / Wei, W. / Xu, Z. / Yao, H. / Yu, S.F. / Zhang, D. / Zhang, H. / Zhang, S. / Zhao, Y. / Zhou, H. / Zhu, X.
History
DepositionOct 21, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 24, 2021Provider: repository / Type: Initial release
Revision 1.1Mar 24, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Oct 18, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)35,8574
Polymers35,2502
Non-polymers6072
Water6,882382
1
A: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,1402
Polymers17,6251
Non-polymers5151
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,7172
Polymers17,6251
Non-polymers921
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)30.278, 41.812, 54.256
Angle α, β, γ (deg.)84.580, 76.300, 89.920
Int Tables number1
Space group name H-MP1

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Components

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


Mass: 17625.037 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRD4, HUNK1 / Plasmid: pET / Production host: Escherichia coli (E. coli) / References: UniProt: O60885
#2: Chemical ChemComp-WEM / methyl 7-(3,5-difluoropyridin-2-yl)-2-methyl-10-[(methylsulfonyl)methyl]-3-oxo-3,4,6,7-tetrahydro-2H-2,4,7-triazadibenzo[cd,f]azulene-9-carboxylate


Mass: 514.501 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H20F2N4O5S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 382 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 1.88 Å3/Da / Density % sol: 34.72 %
Crystal growTemperature: 291 K / Method: evaporation / pH: 8 / Details: 14% w/v PEG 4K, 0.1 M Tris-HCl pH 8

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 1.0332 Å
DetectorType: DECTRIS PILATUS3 X 1M / Detector: PIXEL / Date: Sep 1, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0332 Å / Relative weight: 1
ReflectionResolution: 1.234→52.464 Å / Num. obs: 51557 / % possible obs: 69.7 % / Redundancy: 2.5 % / Biso Wilson estimate: 15.23 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.042 / Rpim(I) all: 0.031 / Rrim(I) all: 0.052 / Net I/σ(I): 9.6 / Num. measured all: 129516
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
1.234-1.2381.81.78195540.7051.542.3640.18.2
5.726-52.4642.60.02719007330.9980.020.03322.798.5

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimlessdata scaling
BUSTERrefinement
PDB_EXTRACT3.25data extraction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3MXF

3mxf


Resolution: 1.286→52.46 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.937 / SU R Cruickshank DPI: 0.071 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.076 / SU Rfree Blow DPI: 0.077 / SU Rfree Cruickshank DPI: 0.074
Details: HYDROGENS WERE FULLY REFINED WITH ZERO OCCUPANCY AT NUCLEAR POSITION. REFINEMENT NOTES. NUMBER OF REFINEMENT NOTES : 1 NOTE 1 : IDEAL-DIST CONTACT TERM CONTACT SETUP. ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY
RfactorNum. reflection% reflectionSelection details
Rfree0.225 2300 4.73 %RANDOM
Rwork0.1928 ---
obs0.1943 48634 74.3 %-
Displacement parametersBiso max: 211.82 Å2 / Biso mean: 20.15 Å2 / Biso min: 8.14 Å2
Baniso -1Baniso -2Baniso -3
1-1.0056 Å20.7598 Å2-0.7381 Å2
2---0.1677 Å2-0.1462 Å2
3----0.8379 Å2
Refine analyzeLuzzati coordinate error obs: 0.19 Å
Refinement stepCycle: final / Resolution: 1.286→52.46 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2108 0 42 382 2532
Biso mean--15.29 30.89 -
Num. residues----253
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d813SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes395HARMONIC5
X-RAY DIFFRACTIONt_it2247HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion292SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies11HARMONIC1
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2544SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2301HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg3160HARMONIC20.93
X-RAY DIFFRACTIONt_omega_torsion3.12
X-RAY DIFFRACTIONt_other_torsion16.12
LS refinement shellResolution: 1.29→1.33 Å / Rfactor Rfree error: 0 / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.3187 56 5.76 %
Rwork0.2551 917 -
all0.2587 973 -
obs--14.23 %
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)
11.5708-0.49281.30710.6391-0.28882.34320.13370.0857-0.0893-0.0178-0.07870.00090.19580.0804-0.0551-0.026-0.0014-0.0075-0.03720.0043-0.051-2.858510.430316.8377
20.8990.03010.13180.45510.01521.1190.0323-0.0239-0.0334-0.0218-0.05470.04290.0786-0.02450.0224-0.01380.0203-0.0156-0.0345-0.0137-0.0431.565631.211541.5732
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A42 - 167
2X-RAY DIFFRACTION2{ B|* }B41 - 167

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