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- PDB-7ymg: Crystal structure of BRD4 bromodomain 1 (BD1) in complex with 2-(... -

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Entry
Database: PDB / ID: 7ymg
TitleCrystal structure of BRD4 bromodomain 1 (BD1) in complex with 2-({3-ethyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl}amino)-3-(1H-indol-3-yl)propan-1-ol
ComponentsBromodomain-containing protein 4
KeywordsTRANSCRIPTION / BRD4 / BET inhibitor / complex
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-JHO / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.4 Å
AuthorsKim, J.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
DepositionJul 28, 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

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)30,99910
Polymers30,0502
Non-polymers9498
Water2,486138
1
A: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,5696
Polymers15,0251
Non-polymers5445
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area130 Å2
ΔGint-10 kcal/mol
Surface area7280 Å2
MethodPISA
2
B: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,4314
Polymers15,0251
Non-polymers4053
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area130 Å2
ΔGint-10 kcal/mol
Surface area7270 Å2
MethodPISA
Unit cell
Length a, b, c (Å)47.573, 32.454, 79.634
Angle α, β, γ (deg.)90.000, 89.970, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

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Protein , 1 types, 2 molecules AB

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


Mass: 15025.235 Da / Num. of mol.: 2 / Fragment: bromodomain 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRD4, HUNK1 / Plasmid: pHis / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: O60885

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Non-polymers , 5 types, 146 molecules

#2: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#3: Chemical ChemComp-JHO / (2S)-2-[(3-ethyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)amino]-3-(1H-indol-3-yl)propan-1-ol


Mass: 336.391 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H20N6O / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-FMT / FORMIC ACID


Mass: 46.025 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: CH2O2
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


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


Mass: 18.015 Da / Num. of mol.: 138 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 39.87 %
Crystal growTemperature: 287 K / Method: vapor diffusion, hanging drop / pH: 7.8
Details: Protein concentration 12 mg/mL Protein Stoarage buffer: 10mM HEPES pH 7.5, 500mM NaCl, 5% Glycerol, 10 mM DTT Reservoir solution: 5M sodium formate, 6% glycerol (Protein/reservoir= ...Details: Protein concentration 12 mg/mL Protein Stoarage buffer: 10mM HEPES pH 7.5, 500mM NaCl, 5% Glycerol, 10 mM DTT Reservoir solution: 5M sodium formate, 6% glycerol (Protein/reservoir= 1000nL/1000nL) co-crystallization: added 5 mM chemical and incubated overnight at 4 celsius.
PH range: 7.0~8.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: PAL/PLS / Beamline: 7A (6B, 6C1) / Wavelength: 0.979 Å
DetectorType: ADSC QUANTUM 270 / Detector: CCD / Date: May 31, 2022
RadiationMonochromator: M / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.4→50 Å / Num. obs: 51025 / % possible obs: 99.5 % / Redundancy: 4.9 % / Biso Wilson estimate: 12.56 Å2 / CC1/2: 0.994 / CC star: 0.998 / Rpim(I) all: 0.033 / Rrim(I) all: 0.073 / Rsym value: 0.052 / Χ2: 0.938 / Net I/σ(I): 24.878
Reflection shellResolution: 1.4→1.42 Å / Redundancy: 4.5 % / Mean I/σ(I) obs: 1.9 / Num. unique obs: 2526 / CC1/2: 0.708 / CC star: 0.911 / Rpim(I) all: 0.442 / Rrim(I) all: 0.971 / Rsym value: 0.723 / Χ2: 0.795 / % possible all: 99.9

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
PHASERphasing
HKL-2000data scaling
HKL-2000data reduction
PDB_EXTRACTdata extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6KEK

6kek


Resolution: 1.4→30.54 Å / SU ML: 0.1192 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 19.4358
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1963 1940 4.24 %
Rwork0.1772 43762 -
obs0.178 45702 94.39 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 15.41 Å2
Refinement stepCycle: LAST / Resolution: 1.4→30.54 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2058 0 67 138 2263
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00632359
X-RAY DIFFRACTIONf_angle_d0.90053238
X-RAY DIFFRACTIONf_chiral_restr0.0736339
X-RAY DIFFRACTIONf_plane_restr0.0062421
X-RAY DIFFRACTIONf_dihedral_angle_d5.2876312
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.4-1.440.2911020.20872234X-RAY DIFFRACTION68.81
1.44-1.470.23741100.19132563X-RAY DIFFRACTION77.28
1.47-1.520.21151210.19582795X-RAY DIFFRACTION85.97
1.52-1.570.22291380.18423033X-RAY DIFFRACTION92.56
1.57-1.620.21711460.17283253X-RAY DIFFRACTION98.35
1.62-1.690.18811450.16773284X-RAY DIFFRACTION99.88
1.69-1.760.17111440.17593273X-RAY DIFFRACTION99.94
1.76-1.860.20831490.17063323X-RAY DIFFRACTION99.88
1.86-1.970.19741430.17293311X-RAY DIFFRACTION99.97
1.97-2.130.18721450.16733284X-RAY DIFFRACTION99.97
2.13-2.340.17281470.17023320X-RAY DIFFRACTION99.97
2.34-2.680.21891420.19013335X-RAY DIFFRACTION99.94
2.68-3.370.20331480.1853361X-RAY DIFFRACTION99.89
3.37-30.540.18171600.1713393X-RAY DIFFRACTION98.39

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