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- PDB-7yq9: Crystal structure of BRD4 bromodomain 1 (BD1) in complex with N-[... -

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Basic information

Entry
Database: PDB / ID: 7yq9
TitleCrystal structure of BRD4 bromodomain 1 (BD1) in complex with N-[2-(1H-indol-3-yl)ethyl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-amine
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-JLX / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.5 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
DepositionAug 5, 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
B: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,9068
Polymers30,0502
Non-polymers8566
Water2,414134
1
A: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,4995
Polymers15,0251
Non-polymers4744
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area110 Å2
ΔGint-7 kcal/mol
Surface area7400 Å2
MethodPISA
2
B: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,4073
Polymers15,0251
Non-polymers3822
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area110 Å2
ΔGint-7 kcal/mol
Surface area7370 Å2
MethodPISA
Unit cell
Length a, b, c (Å)47.498, 32.398, 79.474
Angle α, β, γ (deg.)90.000, 89.990, 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

#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
#2: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#3: Chemical ChemComp-JLX / N-[2-(1H-indol-3-yl)ethyl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-amine


Mass: 346.310 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H13F3N6 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-FMT / FORMIC ACID


Mass: 46.025 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: CH2O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 134 / 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: 2.03 Å3/Da / Density % sol: 39.55 %
Crystal growTemperature: 287 K / Method: vapor diffusion, hanging drop / pH: 7.8
Details: protein concentration 12 mg/mL Protein storage buffer: 10 mM HEPES pH 7.5, 500 mM NaCl, 5% glycerol 10 mM DTT Reservoir solution: 6M sodium formate, 6% glycerol Protein: reservoir solution=1: ...Details: protein concentration 12 mg/mL Protein storage buffer: 10 mM HEPES pH 7.5, 500 mM NaCl, 5% glycerol 10 mM DTT Reservoir solution: 6M sodium formate, 6% glycerol Protein: reservoir solution=1:1 co-crystallization: added 5mM 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: 11C / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Mar 23, 2022
RadiationMonochromator: M / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.5→50 Å / Num. obs: 38524 / % possible obs: 97.6 % / Redundancy: 6.6 % / Biso Wilson estimate: 12.28 Å2 / CC1/2: 0.999 / CC star: 1 / Rpim(I) all: 0.025 / Rrim(I) all: 0.066 / Rsym value: 0.061 / Χ2: 0.987 / Net I/σ(I): 25.85
Reflection shellResolution: 1.5→1.53 Å / Redundancy: 5.8 % / Mean I/σ(I) obs: 5.4 / Num. unique obs: 1795 / CC1/2: 0.962 / CC star: 0.99 / Rpim(I) all: 0.123 / Rrim(I) all: 0.314 / Rsym value: 0.289 / Χ2: 0.911 / % possible all: 89.9

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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: 1.5→47.5 Å / SU ML: 0.1353 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 18.6263
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2005 1995 5.37 %
Rwork0.1791 35179 -
obs0.1803 37174 93.82 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 14.28 Å2
Refinement stepCycle: LAST / Resolution: 1.5→47.5 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2058 0 58 134 2250
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00682250
X-RAY DIFFRACTIONf_angle_d0.94133086
X-RAY DIFFRACTIONf_chiral_restr0.0745323
X-RAY DIFFRACTIONf_plane_restr0.0067395
X-RAY DIFFRACTIONf_dihedral_angle_d10.345290
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.5-1.530.20651110.18271924X-RAY DIFFRACTION71.83
1.53-1.570.24491200.18272188X-RAY DIFFRACTION83.99
1.57-1.620.21441330.18082359X-RAY DIFFRACTION87.59
1.62-1.670.2121410.17562445X-RAY DIFFRACTION93.19
1.67-1.730.18741420.17522538X-RAY DIFFRACTION95.92
1.73-1.80.20681550.16832639X-RAY DIFFRACTION98.55
1.8-1.880.18771490.17172616X-RAY DIFFRACTION98.47
1.88-1.980.19611450.16272610X-RAY DIFFRACTION97.76
1.98-2.110.16761460.16182549X-RAY DIFFRACTION96.7
2.11-2.270.16661520.1652691X-RAY DIFFRACTION98.78
2.27-2.50.2121490.18942662X-RAY DIFFRACTION98.77
2.5-2.860.21221490.18192578X-RAY DIFFRACTION96.74
2.86-3.60.2061530.19182696X-RAY DIFFRACTION98.99
3.6-47.50.20681500.18472684X-RAY DIFFRACTION95.91

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