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- PDB-4nyw: Crystal Structure of the Bromodomain of human CREBBP in complex w... -

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Basic information

Entry
Database: PDB / ID: 4nyw
TitleCrystal Structure of the Bromodomain of human CREBBP in complex with a dihydroquinoxalinone ligand
ComponentsCREB-binding protein
KeywordsTRANSCRIPTION / CREBBP / CREB BINDING / KAT3A / RSTS / RST / BROMODOMAIN / Structural Genomics Consortium / SGC
Function / homology
Function and homology information


peptide lactyltransferase (CoA-dependent) activity / NFE2L2 regulating ER-stress associated genes / peptide N-acetyltransferase activity / Activation of the TFAP2 (AP-2) family of transcription factors / NFE2L2 regulating inflammation associated genes / regulation of smoothened signaling pathway / histone H3K18 acetyltransferase activity / LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production / N-terminal peptidyl-lysine acetylation / histone H3K27 acetyltransferase activity ...peptide lactyltransferase (CoA-dependent) activity / NFE2L2 regulating ER-stress associated genes / peptide N-acetyltransferase activity / Activation of the TFAP2 (AP-2) family of transcription factors / NFE2L2 regulating inflammation associated genes / regulation of smoothened signaling pathway / histone H3K18 acetyltransferase activity / LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production / N-terminal peptidyl-lysine acetylation / histone H3K27 acetyltransferase activity / NFE2L2 regulates pentose phosphate pathway genes / NFE2L2 regulating MDR associated enzymes / MRF binding / RUNX1 regulates transcription of genes involved in differentiation of myeloid cells / Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells / RUNX3 regulates NOTCH signaling / Regulation of FOXO transcriptional activity by acetylation / NOTCH4 Intracellular Domain Regulates Transcription / Regulation of gene expression by Hypoxia-inducible Factor / Nuclear events mediated by NFE2L2 / Regulation of NFE2L2 gene expression / negative regulation of transcription by RNA polymerase I / NOTCH3 Intracellular Domain Regulates Transcription / NFE2L2 regulating anti-oxidant/detoxification enzymes / TRAF6 mediated IRF7 activation / NFE2L2 regulating tumorigenic genes / peptide-lysine-N-acetyltransferase activity / FOXO-mediated transcription of cell death genes / embryonic digit morphogenesis / homeostatic process / protein acetylation / Notch-HLH transcription pathway / positive regulation of transforming growth factor beta receptor signaling pathway / Formation of paraxial mesoderm / non-canonical NF-kappaB signal transduction / Zygotic genome activation (ZGA) / stimulatory C-type lectin receptor signaling pathway / cellular response to nutrient levels / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / acetyltransferase activity / positive regulation of double-strand break repair via homologous recombination / histone acetyltransferase complex / Attenuation phase / regulation of cellular response to heat / histone acetyltransferase activity / histone acetyltransferase / Transferases; Acyltransferases; Transferring groups other than aminoacyl groups / RORA activates gene expression / NPAS4 regulates expression of target genes / Regulation of lipid metabolism by PPARalpha / CD209 (DC-SIGN) signaling / BMAL1:CLOCK,NPAS2 activates circadian gene expression / SUMOylation of transcription cofactors / Activation of gene expression by SREBF (SREBP) / Formation of the beta-catenin:TCF transactivating complex / Heme signaling / protein destabilization / Transcriptional activation of mitochondrial biogenesis / PPARA activates gene expression / Evasion by RSV of host interferon responses / Cytoprotection by HMOX1 / NOTCH1 Intracellular Domain Regulates Transcription / chromatin DNA binding / Pre-NOTCH Transcription and Translation / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / transcription coactivator binding / Transcriptional regulation of white adipocyte differentiation / Activation of anterior HOX genes in hindbrain development during early embryogenesis / positive regulation of protein localization to nucleus / transcription corepressor activity / cellular response to UV / rhythmic process / Circadian Clock / p53 binding / TRAF3-dependent IRF activation pathway / HATs acetylate histones / protein-containing complex assembly / DNA-binding transcription factor binding / Estrogen-dependent gene expression / RNA polymerase II-specific DNA-binding transcription factor binding / transcription regulator complex / damaged DNA binding / transcription coactivator activity / nuclear body / response to hypoxia / chromatin binding / regulation of DNA-templated transcription / chromatin / SARS-CoV-2 activates/modulates innate and adaptive immune responses / positive regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / signal transduction / positive regulation of transcription by RNA polymerase II / zinc ion binding / nucleoplasm / nucleus / cytoplasm / cytosol
Similarity search - Function
Nuclear receptor coactivator, CREB-bp-like, interlocking / Nuclear receptor coactivator, CREB-bp-like, interlocking domain superfamily / Creb binding / Zinc finger, TAZ-type / TAZ domain superfamily / TAZ zinc finger / Zinc finger TAZ-type profile. / TAZ zinc finger, present in p300 and CBP / Coactivator CBP, KIX domain / CREB-binding protein/p300, atypical RING domain ...Nuclear receptor coactivator, CREB-bp-like, interlocking / Nuclear receptor coactivator, CREB-bp-like, interlocking domain superfamily / Creb binding / Zinc finger, TAZ-type / TAZ domain superfamily / TAZ zinc finger / Zinc finger TAZ-type profile. / TAZ zinc finger, present in p300 and CBP / Coactivator CBP, KIX domain / CREB-binding protein/p300, atypical RING domain / CBP/p300-type histone acetyltransferase domain / CBP/p300, atypical RING domain superfamily / KIX domain / CREB-binding protein/p300, atypical RING domain / KIX domain profile. / CBP/p300-type histone acetyltransferase (HAT) domain profile. / Histone acetyltransferase Rtt109/CBP / Histone acetylation protein / Histone acetylation protein / Coactivator CBP, KIX domain superfamily / Zinc finger ZZ-type signature. / Zinc-binding domain, present in Dystrophin, CREB-binding protein. / Zinc finger, ZZ type / Zinc finger, ZZ-type / Zinc finger, ZZ-type superfamily / Zinc finger ZZ-type profile. / Nuclear receptor coactivator, interlocking / Bromodomain-like / Histone Acetyltransferase; Chain A / Bromodomain, conserved site / Bromodomain signature. / Bromodomain / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily / Zinc finger, RING/FYVE/PHD-type / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-2O3 / THIOCYANATE ION / CREB-binding protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.43 Å
AuthorsFilippakopoulos, P. / Picaud, S. / Felletar, I. / Rooney, T.P.C. / Fedorov, O. / Martin, S. / Monteiro, O.P. / Conway, S.J. / von Delft, F. / Brennan, P. ...Filippakopoulos, P. / Picaud, S. / Felletar, I. / Rooney, T.P.C. / Fedorov, O. / Martin, S. / Monteiro, O.P. / Conway, S.J. / von Delft, F. / Brennan, P. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C. / Knapp, S. / Structural Genomics Consortium (SGC)
CitationJournal: TO BE PUBLISHED
Title: Crystal Structure of the Bromodomain of human CREBBP in complex with a dihydroquinoxalinone ligand
Authors: Filippakopoulos, P. / Picaud, S. / Felletar, I. / Rooney, T.P.C. / Fedorov, O. / Martin, S. / Monteiro, O.P. / Conway, S.J. / von Delft, F. / Brennan, P. / Arrowsmith, C.H. / Edwards, A.M. / ...Authors: Filippakopoulos, P. / Picaud, S. / Felletar, I. / Rooney, T.P.C. / Fedorov, O. / Martin, S. / Monteiro, O.P. / Conway, S.J. / von Delft, F. / Brennan, P. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C. / Knapp, S.
History
DepositionDec 11, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 29, 2014Provider: repository / Type: Initial release
Revision 1.1Jan 31, 2018Group: Database references / Structure summary / Category: audit_author / citation_author / Item: _audit_author.name / _citation_author.name
Revision 1.2Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: CREB-binding protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,7845
Polymers14,2231
Non-polymers5614
Water3,351186
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)34.966, 49.917, 80.160
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 CREB-binding protein


Mass: 14223.349 Da / Num. of mol.: 1 / Fragment: UNP residues 1081-1197
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CBP, CREBBP / Plasmid: pNIC28-Bsa4 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)-R3 / References: UniProt: Q92793
#2: Chemical ChemComp-SCN / THIOCYANATE ION


Mass: 58.082 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: CNS
#3: Chemical ChemComp-2O3 / (3R)-N-[3-(3,4-dihydroquinolin-1(2H)-yl)propyl]-3-methyl-2-oxo-1,2,3,4-tetrahydroquinoxaline-5-carboxamide


Mass: 378.467 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H26N4O2
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 186 / Source method: isolated from a natural source / Formula: H2O

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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: 2.46 Å3/Da / Density % sol: 49.98 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 20% PEG 3350, 9% Ethylene Glycol, 0.18M KSCN, pH 7.5, VAPOR DIFFUSION, SITTING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.9173 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Jul 13, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9173 Å / Relative weight: 1
ReflectionRedundancy: 11.7 % / Av σ(I) over netI: 5.8 / Number: 309695 / Rsym value: 0.097 / D res high: 1.425 Å / D res low: 19.692 Å / Num. obs: 26470 / % possible obs: 98.4
Diffraction reflection shell
Highest resolution (Å)Lowest resolution (Å)% possible obs (%)IDRmerge(I) obsRsym valueRedundancy
4.5119.6998.910.0590.05913.4
3.194.5110010.0470.04713.8
2.63.1999.910.0640.06414.2
2.252.699.710.0840.08415.1
2.022.2599.310.1160.11614
1.842.0299.410.1950.19514.6
1.71.8498.410.3050.30513.9
1.591.798.910.4340.4349.5
1.51.5995.510.640.646.9
1.421.597.210.8660.8667.4
ReflectionResolution: 1.42→19.69 Å / Num. all: 26900 / Num. obs: 26470 / % possible obs: 98.4 % / Redundancy: 11.7 % / Biso Wilson estimate: 14 Å2 / Rmerge(I) obs: 0.097 / Rsym value: 0.097 / Net I/σ(I): 15.1
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique allRsym value% possible all
1.42-1.57.40.866237480.86698.4
1.5-1.596.90.642.834740.6498.6
1.59-1.79.50.4344.834000.43499.3
1.7-1.8413.90.3058.431660.30599.3
1.84-2.0214.60.19512.629630.19599.6
2.02-2.25140.1161926840.11699.6
2.25-2.615.10.08426.623950.08499.7
2.6-3.1914.20.06433.320610.06499.7
3.19-4.5113.80.04746.716280.04799.6
4.51-19.6913.40.05945.49510.05998.9

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Phasing

PhasingMethod: molecular replacement
Phasing MRRfactor: 59.67 / Model details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation3.5 Å19.54 Å
Translation3.5 Å19.54 Å

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Processing

Software
NameVersionClassificationNB
SCALA3.3.16data scaling
PHASER2.1.4phasing
REFMACrefinement
PDB_EXTRACT3.11data extraction
DNAdata collection
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: Ensemble of PDB entries 3DAI, 3HMH, 2GRC, 2OO1, 2OSS, 2OUO, 3D7C, and 3DWY

3dai

3hmh

2grc

2oo1

2oss

2ouo

3d7c

3dwy


Resolution: 1.43→19.69 Å / Cor.coef. Fo:Fc: 0.97 / Cor.coef. Fo:Fc free: 0.959 / WRfactor Rfree: 0.175 / WRfactor Rwork: 0.1516 / Occupancy max: 1 / Occupancy min: 0.3 / FOM work R set: 0.9017 / SU B: 1.785 / SU ML: 0.036 / SU R Cruickshank DPI: 0.0581 / SU Rfree: 0.0599 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.058 / ESU R Free: 0.06 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.1867 1330 5 %RANDOM
Rwork0.1625 ---
obs0.1638 26424 98.08 %-
all-26941 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 103.49 Å2 / Biso mean: 17.8195 Å2 / Biso min: 6.96 Å2
Baniso -1Baniso -2Baniso -3
1-0.94 Å20 Å20 Å2
2--0.31 Å20 Å2
3----1.25 Å2
Refinement stepCycle: LAST / Resolution: 1.43→19.69 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms968 0 39 186 1193
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0221056
X-RAY DIFFRACTIONr_bond_other_d0.0050.02749
X-RAY DIFFRACTIONr_angle_refined_deg1.5292.0081431
X-RAY DIFFRACTIONr_angle_other_deg1.1253.0081823
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4825119
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.5312554
X-RAY DIFFRACTIONr_dihedral_angle_3_deg10.7715180
X-RAY DIFFRACTIONr_dihedral_angle_4_deg10.711156
X-RAY DIFFRACTIONr_chiral_restr0.0920.2146
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0211145
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02210
LS refinement shellResolution: 1.43→1.462 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.3 84 -
Rwork0.28 1637 -
all-1721 -
obs--95.19 %
Refinement TLS params.Method: refined / Origin x: 30.2455 Å / Origin y: 28.1319 Å / Origin z: 7.2542 Å
111213212223313233
T0.0379 Å20.0052 Å2-0.0065 Å2-0.0252 Å20.0053 Å2--0.0242 Å2
L0.3073 °2-0.0031 °20.4112 °2-0.2139 °2-0.247 °2--0.8712 °2
S0.029 Å °-0.0142 Å °-0.02 Å °0.003 Å °0.0112 Å °0.0166 Å °0.0442 Å °-0.0357 Å °-0.0402 Å °

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