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- PDB-5nrw: Crystal structure of the human bromodomain of CREBBP bound to the... -

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Basic information

Entry
Database: PDB / ID: 5nrw
TitleCrystal structure of the human bromodomain of CREBBP bound to the inhibitor XDM4
ComponentsCREB-binding protein
KeywordsTRANSCRIPTION / bromodomain / protein-inhibitor complex / CBP / epigenetics
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 / histone H3K18 acetyltransferase activity / regulation of smoothened signaling pathway / N-terminal peptidyl-lysine acetylation / histone H3K27 acetyltransferase activity / LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production ...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 / histone H3K18 acetyltransferase activity / regulation of smoothened signaling pathway / N-terminal peptidyl-lysine acetylation / histone H3K27 acetyltransferase activity / LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production / 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 FOXO transcriptional activity by acetylation / Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells / RUNX3 regulates NOTCH signaling / Regulation of gene expression by Hypoxia-inducible Factor / Nuclear events mediated by NFE2L2 / NOTCH4 Intracellular Domain Regulates Transcription / Regulation of NFE2L2 gene expression / negative regulation of transcription by RNA polymerase I / NOTCH3 Intracellular Domain Regulates Transcription / TRAF6 mediated IRF7 activation / FOXO-mediated transcription of cell death genes / peptide-lysine-N-acetyltransferase activity / NFE2L2 regulating tumorigenic genes / NFE2L2 regulating anti-oxidant/detoxification enzymes / 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 / stimulatory C-type lectin receptor signaling pathway / acetyltransferase activity / Zygotic genome activation (ZGA) / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / histone acetyltransferase complex / Attenuation phase / positive regulation of double-strand break repair via homologous recombination / cellular response to nutrient levels / Transcriptional and post-translational regulation of MITF-M expression and activity / canonical NF-kappaB signal transduction / histone acetyltransferase activity / regulation of cellular response to heat / histone acetyltransferase / RORA activates gene expression / Transferases; Acyltransferases; Transferring groups other than aminoacyl groups / Regulation of lipid metabolism by PPARalpha / NPAS4 regulates expression of target genes / 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 / Cytoprotection by HMOX1 / chromatin DNA binding / Evasion by RSV of host interferon responses / NOTCH1 Intracellular Domain Regulates Transcription / transcription coactivator binding / Pre-NOTCH Transcription and Translation / Transcriptional regulation of white adipocyte differentiation / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / positive regulation of protein localization to nucleus / Activation of anterior HOX genes in hindbrain development during early embryogenesis / transcription corepressor activity / cellular response to UV / p53 binding / Circadian Clock / rhythmic process / 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 / response to hypoxia / nuclear body / 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 / cytosol / cytoplasm
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-96N / CREB-binding protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.7 Å
AuthorsHuegle, M. / Wohlwend, D.
Funding support Germany, 1items
OrganizationGrant numberCountry
German Research FoundationWO 2012/1-1 Germany
CitationJournal: Angew. Chem. Int. Ed. Engl. / Year: 2017
Title: Beyond the BET Family: Targeting CBP/p300 with 4-Acyl Pyrroles.
Authors: Hugle, M. / Lucas, X. / Ostrovskyi, D. / Regenass, P. / Gerhardt, S. / Einsle, O. / Hau, M. / Jung, M. / Breit, B. / Gunther, S. / Wohlwend, D.
History
DepositionApr 25, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 16, 2017Provider: repository / Type: Initial release
Revision 1.1Oct 11, 2017Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 1.2Jan 17, 2024Group: 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 / pdbx_struct_special_symmetry
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: CREB-binding protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,8066
Polymers14,2231
Non-polymers5835
Water3,063170
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: light scattering, Right-Angle Light Scattering proved monomeric state
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area400 Å2
ΔGint4 kcal/mol
Surface area7370 Å2
MethodPISA
Unit cell
Length a, b, c (Å)90.030, 34.130, 40.290
Angle α, β, γ (deg.)90.000, 92.650, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-1327-

HOH

21A-1441-

HOH

31A-1468-

HOH

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Components

#1: Protein CREB-binding protein


Mass: 14223.349 Da / Num. of mol.: 1 / Fragment: bromodomain, UNP residues 1081-1197
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CREBBP, CBP / Plasmid: pNIC28-Bsa4 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q92793, histone acetyltransferase
#2: Chemical ChemComp-96N / 4-ethanoyl-3-ethyl-5-methyl-~{N}-(naphthalen-1-ylmethyl)-1~{H}-pyrrole-2-carboxamide / XDM4


Mass: 334.412 Da / Num. of mol.: 1 / Fragment: XDM4 / Source method: obtained synthetically / Formula: C21H22N2O2
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 170 / 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: 2.25 Å3/Da / Density % sol: 45.42 % / Mosaicity: 0.29 °
Crystal growTemperature: 277 K / Method: evaporation / pH: 6.5 / Details: LiSO4, PEG 3350, ethylene glycol

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Feb 21, 2015
RadiationMonochromator: Fixed-exit LN2 cooled Double Crystal Monochromator
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.7→44.97 Å / Num. obs: 12221 / % possible obs: 89.9 % / Redundancy: 2.4 % / CC1/2: 0.989 / Rmerge(I) obs: 0.066 / Rpim(I) all: 0.051 / Rrim(I) all: 0.084 / Net I/σ(I): 10.2
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsCC1/2Rpim(I) allRrim(I) all% possible all
1.7-1.732.30.1380.9240.1080.17791.9
9-44.972.40.0840.9590.0640.10681.1

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation1.7 Å44.97 Å
Translation1.7 Å44.97 Å

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Processing

Software
NameVersionClassification
Aimless0.5.17data scaling
PHASER2.5.7phasing
REFMAC5.8.0135refinement
PDB_EXTRACT3.22data extraction
MOSFLMdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3DWY

3dwy


Resolution: 1.7→44.97 Å / Cor.coef. Fo:Fc: 0.917 / Cor.coef. Fo:Fc free: 0.901 / SU B: 5.281 / SU ML: 0.099 / SU R Cruickshank DPI: 0.1672 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.167 / ESU R Free: 0.151
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2599 704 5.8 %RANDOM
Rwork0.2193 ---
obs0.2218 11516 89.43 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 58.25 Å2 / Biso mean: 17.886 Å2 / Biso min: 6.68 Å2
Baniso -1Baniso -2Baniso -3
1--0.54 Å2-0 Å20.2 Å2
2--1.9 Å20 Å2
3----1.37 Å2
Refinement stepCycle: final / Resolution: 1.7→44.97 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms966 0 41 170 1177
Biso mean--20.92 25.88 -
Num. residues----115
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.021061
X-RAY DIFFRACTIONr_bond_other_d0.0020.021005
X-RAY DIFFRACTIONr_angle_refined_deg1.5142.011438
X-RAY DIFFRACTIONr_angle_other_deg0.97632320
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.5935120
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.75824.90653
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.71715183
X-RAY DIFFRACTIONr_dihedral_angle_4_deg11.565156
X-RAY DIFFRACTIONr_chiral_restr0.0850.2145
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0211182
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02241
LS refinement shellResolution: 1.7→1.744 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.27 44 -
Rwork0.225 864 -
all-908 -
obs--92.37 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
14.6998-2.41791.82069.7459-2.06436.96910.26060.17050.4845-0.6765-0.31390.1104-0.55090.08660.05320.2134-0.01330.02190.18040.01890.12315.165835.405837.3325
22.851-4.64682.24928.9225-6.73738.77770.16210.0717-0.2022-0.3286-0.02790.3190.288-0.1058-0.13420.0495-0.0055-0.00250.1067-0.00560.04312.815225.139142.7629
33.6951-0.8362-0.9043.5046-0.20786.22950.02860.2348-0.2175-0.0834-0.0780.06330.2897-0.39810.04950.0439-0.013-0.03070.035-0.0150.042110.488316.424855.536
42.739-0.1940.25198.2185-2.30314.01320.0029-0.072-0.12240.6106-0.15060.44020.0725-0.4970.14770.0863-0.01340.05890.1597-0.03130.05792.600422.499367.3049
51.9238-1.16513.9211.3892-1.87888.35430.0381-0.0739-0.1817-0.15530.19930.2813-0.0281-0.0545-0.23740.033-0.0096-0.04630.1110.01250.07443.267825.601948.5813
61.9498-0.76342.12772.976-2.7067.7158-0.05940.04390.1610.08230.17440.0573-0.6099-0.1133-0.11490.06660.00980.02010.02430.00530.036410.428630.88455.3413
71.55841.20640.66047.3937-5.19236.43140.04150.0098-0.2182-0.03-0.1713-0.26050.0640.3840.12980.00920.0131-0.0170.070.01010.066419.157421.982160.3981
89.89850.11850.46089.5267-2.940210.08860.29190.57710.565-0.3422-0.1584-0.436-0.46310.2197-0.13350.109-0.040.04970.13050.00490.094818.119933.973442.5904
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1083 - 1091
2X-RAY DIFFRACTION2A1092 - 1101
3X-RAY DIFFRACTION3A1102 - 1118
4X-RAY DIFFRACTION4A1119 - 1131
5X-RAY DIFFRACTION5A1132 - 1147
6X-RAY DIFFRACTION6A1148 - 1168
7X-RAY DIFFRACTION7A1169 - 1187
8X-RAY DIFFRACTION8A1188 - 1197

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