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- PDB-7axr: Crystal structure of BRD4(1) bound to the dual BET-HDAC inhibitor... -

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Basic information

Entry
Database: PDB / ID: 7axr
TitleCrystal structure of BRD4(1) bound to the dual BET-HDAC inhibitor LSH24
ComponentsBromodomain-containing protein 4
KeywordsPROTEIN BINDING / BRD4(1) / BRD4 / BD1 / first Bromodomain / Bromodomain / BET / HDAC / BETi / HDACi / dual Inhibitor / LSH24
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-S7T / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.5 Å
AuthorsHuegle, M.
Funding support Germany, 1items
OrganizationGrant numberCountry
German Research Foundation (DFG)GU1225 3 1 Germany
CitationJournal: J.Med.Chem. / Year: 2021
Title: 4-Acyl Pyrrole Capped HDAC Inhibitors: A New Scaffold for Hybrid Inhibitors of BET Proteins and Histone Deacetylases as Antileukemia Drug Leads.
Authors: Schaker-Hubner, L. / Warstat, R. / Ahlert, H. / Mishra, P. / Kraft, F.B. / Schliehe-Diecks, J. / Scholer, A. / Borkhardt, A. / Breit, B. / Bhatia, S. / Hugle, M. / Gunther, S. / Hansen, F.K.
History
DepositionNov 10, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 6, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 13, 2021Group: Data collection / Database references
Category: citation / citation_author ...citation / citation_author / database_PDB_rev / database_PDB_rev_record / pdbx_database_proc
Item: _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.2Oct 27, 2021Group: Data collection / Database references / Category: citation / pdbx_database_proc
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)15,8143
Polymers15,0991
Non-polymers7152
Water2,828157
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area7370 Å2
MethodPISA
Unit cell
Length a, b, c (Å)37.590, 43.796, 78.438
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 15099.380 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRD4, HUNK1 / Plasmid: pNIC28-bsa4::BRD4 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: O60885
#2: Chemical ChemComp-S7T / 4-acetyl-3-ethyl-N-(3-(3-(hydroxyamino)-3-oxopropyl)phenyl)-5-methyl-1H-pyrrole-2-carboxamide / 4-ethanoyl-3-ethyl-5-methyl-~{N}-[3-[3-(oxidanylamino)-3-oxidanylidene-propyl]phenyl]-1~{H}-pyrrole-2-carboxamide


Mass: 357.404 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H23N3O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 157 / 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: 2.14 Å3/Da / Density % sol: 42.47 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7 / Details: 35% Tacsimate pH 7.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 1.000031 Å
DetectorType: DECTRIS PILATUS 2M-F / Detector: PIXEL / Date: May 13, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.000031 Å / Relative weight: 1
ReflectionResolution: 1.5→39.22 Å / Num. obs: 20855 / % possible obs: 97.6 % / Redundancy: 8.7 % / CC1/2: 0.999 / Rmerge(I) obs: 0.068 / Rpim(I) all: 0.024 / Rrim(I) all: 0.073 / Net I/σ(I): 18 / Num. measured all: 181504
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
1.5-1.5390.85787879810.8480.3020.912.595.5
8.22-39.226.40.023105916610.010.02656.199.4

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation3.39 Å39.22 Å
Translation3.39 Å39.22 Å

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Processing

Software
NameVersionClassification
PHENIX1.18.2-3874refinement
XDSdata reduction
Aimless0.7.4data scaling
PHASER2.8.3phasing
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4LYW

4lyw


Resolution: 1.5→39.22 Å / SU ML: 0.15 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 26.52 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2267 1028 4.94 %
Rwork0.1914 19774 -
obs0.1931 20802 97.21 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 69.06 Å2 / Biso mean: 24.0918 Å2 / Biso min: 11.89 Å2
Refinement stepCycle: final / Resolution: 1.5→39.22 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1056 0 52 172 1280
Biso mean--22.73 33.85 -
Num. residues----127
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 7

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.5-1.580.30671380.29982722286096
1.58-1.680.27421360.25222754289096
1.68-1.810.2881550.23812760291597
1.81-1.990.23931540.2142807296197
1.99-2.280.22541530.19072786293998
2.28-2.870.26091490.1942897304698
2.87-39.220.17891430.1593048319199

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