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- PDB-8gpz: Crystal structure of BRD4 bromodomain 1 (BD1) in complex with C23... -

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Basic information

Entry
Database: PDB / ID: 8gpz
TitleCrystal structure of BRD4 bromodomain 1 (BD1) in complex with C239-0012
ComponentsBromodomain-containing protein 4
KeywordsTRANSCRIPTION / BD1 / complex / inhibitor
Function / homology
Function and homology information


histone H4K8ac reader activity / RNA polymerase II C-terminal domain binding / histone H3K27ac reader activity / negative regulation of DNA damage checkpoint / P-TEFb complex binding / histone H3K9ac reader activity / histone H4 reader activity / histone H4K5ac reader activity / histone H4K12ac reader activity / host-mediated suppression of viral transcription ...histone H4K8ac reader activity / RNA polymerase II C-terminal domain binding / histone H3K27ac reader activity / negative regulation of DNA damage checkpoint / P-TEFb complex binding / histone H3K9ac reader activity / histone H4 reader activity / histone H4K5ac reader activity / histone H4K12ac reader activity / host-mediated suppression of viral transcription / histone H4K16ac reader activity / positive regulation of G2/M transition of mitotic cell cycle / positive regulation of T-helper 17 cell lineage commitment / RNA polymerase II CTD heptapeptide repeat kinase activity / condensed nuclear chromosome / transcription coregulator activity / positive regulation of transcription elongation by RNA polymerase II / p53 binding / Regulation of PD-L1(CD274) transcription / regulation of inflammatory response / chromosome / histone binding / Potential therapeutics for SARS / positive regulation of canonical NF-kappaB signal transduction / transcription coactivator activity / transcription cis-regulatory region binding / chromatin remodeling / protein serine/threonine kinase activity / chromatin binding / regulation of transcription by RNA polymerase II / DNA damage response / positive regulation of DNA-templated transcription / chromatin / enzyme binding / positive regulation of transcription by RNA polymerase II / DNA-templated transcription / nucleoplasm / nucleus
Similarity search - Function
Bromodomain protein 4, C-terminal / C-terminal domain of bromodomain protein 4 / Brdt, bromodomain, repeat I / Brdt, bromodomain, repeat II / NET domain superfamily / NET domain profile. / : / NET domain / Bromodomain extra-terminal - transcription regulation / Bromodomain-like ...Bromodomain protein 4, C-terminal / C-terminal domain of bromodomain protein 4 / Brdt, bromodomain, repeat I / Brdt, bromodomain, repeat II / NET domain superfamily / NET domain profile. / : / NET domain / Bromodomain extra-terminal - transcription regulation / Bromodomain-like / Histone Acetyltransferase; Chain A / Bromodomain, conserved site / Bromodomain signature. / Bromodomain / bromo domain / Bromodomain / Bromodomain (BrD) profile. / Bromodomain-like superfamily / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
FORMIC ACID / Chem-KC3 / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.528 Å
AuthorsPark, T.H. / Lee, B.I.
Funding support Korea, Republic Of, 2items
OrganizationGrant numberCountry
National Research Foundation (NRF, Korea)NRF-2019R1A2C1002545 Korea, Republic Of
National Research Foundation (NRF, Korea)NRF-2018R1A5A2023127 Korea, Republic Of
CitationJournal: Sci Rep / Year: 2023
Title: Crystal structure of [1,2,4]triazolo[4,3-b]pyridazine derivatives as BRD4 bromodomain inhibitors and structure-activity relationship study.
Authors: Kim, J.H. / Pandit, N. / Yoo, M. / Park, T.H. / Choi, J.U. / Park, C.H. / Jung, K.Y. / Lee, B.I.
History
DepositionAug 27, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 18, 2023Provider: repository / Type: Initial release
Revision 1.1Aug 2, 2023Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Nov 29, 2023Group: 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)15,1005
Polymers14,7541
Non-polymers3464
Water1,54986
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area420 Å2
ΔGint-9 kcal/mol
Surface area7220 Å2
Unit cell
Length a, b, c (Å)32.158, 47.318, 79.540
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: 14754.074 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRD4, HUNK1 / Production host: Escherichia coli (E. coli) / References: UniProt: O60885
#2: Chemical ChemComp-FMT / FORMIC ACID


Mass: 46.025 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: CH2O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-KC3 / 3-methyl-6-(4-methylpiperidin-1-yl)-[1,2,4]triazolo[4,3-b]pyridazine


Mass: 231.297 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H17N5 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 86 / 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: 2.05 Å3/Da / Density % sol: 40.02 %
Crystal growTemperature: 287 K / Method: vapor diffusion, hanging drop / Details: 6 M Sodium formate, 10% Glycerol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: PAL/PLS / Beamline: 11C / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Mar 5, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.528→50 Å / Num. obs: 18654 / % possible obs: 97.7 % / Redundancy: 6.2 % / CC1/2: 0.999 / Rpim(I) all: 0.041 / Rrim(I) all: 0.104 / Rsym value: 0.095 / Net I/σ(I): 17.222
Reflection shellResolution: 1.53→1.56 Å / Redundancy: 5.1 % / Mean I/σ(I) obs: 2 / Num. unique obs: 791 / CC1/2: 0.782 / Rpim(I) all: 0.314 / Rrim(I) all: 0.762 / Rsym value: 0.691 / % possible all: 86.2

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Processing

Software
NameVersionClassification
PHENIX1.14_3260refinement
PDB_EXTRACT3.27data extraction
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6kei

6kei


Resolution: 1.528→40.666 Å / SU ML: 0.15 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 21.83 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2118 837 5.02 %
Rwork0.1859 15850 -
obs0.1872 16687 87.64 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 35.74 Å2 / Biso mean: 14.9001 Å2 / Biso min: 7.21 Å2
Refinement stepCycle: final / Resolution: 1.528→40.666 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1019 0 24 86 1129
Biso mean--16.11 21.93 -
Num. residues----124
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.5284-1.62410.23771080.1904174760
1.6241-1.74950.24381170.2014220375
1.7495-1.92560.24951350.2019276393
1.9256-2.20420.24051570.1836297799
2.2042-2.7770.22361370.18883036100
2.777-40.6660.18421830.1785312499

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