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- PDB-5nu3: Crystal structure of the human bromodomain of CREBBP bound to the... -

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Basic information

Entry
Database: PDB / ID: 5nu3
TitleCrystal structure of the human bromodomain of CREBBP bound to the inhibitor XDM-CBP
ComponentsCREB-binding protein
KeywordsTRANSFERASE / bromodomain / protein-inhibitor complex / epigenetics / CREBBP
Function / homology
Function and homology information


peptide lactyltransferase 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 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 / NOTCH4 Intracellular Domain Regulates Transcription / Regulation of FOXO transcriptional activity by acetylation / 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 / FOXO-mediated transcription of cell death genes / NFE2L2 regulating tumorigenic genes / peptide-lysine-N-acetyltransferase activity / embryonic digit morphogenesis / homeostatic process / protein acetylation / Notch-HLH transcription pathway / Formation of paraxial mesoderm / positive regulation of transforming growth factor beta receptor signaling pathway / non-canonical NF-kappaB signal transduction / Zygotic genome activation (ZGA) / stimulatory C-type lectin receptor signaling pathway / acetyltransferase activity / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / cellular response to nutrient levels / 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) / Evasion by RSV of host interferon responses / Formation of the beta-catenin:TCF transactivating complex / Heme signaling / protein destabilization / Transcriptional activation of mitochondrial biogenesis / PPARA activates gene expression / 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 / chromatin / regulation of DNA-templated transcription / 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 / Coactivator CBP, KIX domain superfamily / Histone acetylation protein / Histone acetylation protein / 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-99E / (R,R)-2,3-BUTANEDIOL / CREB-binding protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.75 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 28, 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 / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
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)15,0467
Polymers14,2231
Non-polymers8236
Water3,225179
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: light scattering, BD of CREBBP is a monomer in solution as demonstrated by Right-Angle Light Scattering (RALS)
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area980 Å2
ΔGint-4 kcal/mol
Surface area7470 Å2
MethodPISA
Unit cell
Length a, b, c (Å)35.860, 49.240, 80.510
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: bromodomain
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-99E / ~{N}-[[2,8-bis(oxidanyl)naphthalen-1-yl]methyl]-4-ethanoyl-3-ethyl-5-methyl-1~{H}-pyrrole-2-carboxamide


Mass: 366.410 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H22N2O4
#3: Chemical
ChemComp-BU3 / (R,R)-2,3-BUTANEDIOL


Mass: 90.121 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C4H10O2
#4: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 179 / 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: 2.5 Å3/Da / Density % sol: 50.77 % / Mosaicity: 0.59 °
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: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.54187 Å
DetectorType: MAR scanner 345 mm plate / Detector: IMAGE PLATE / Date: Nov 24, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54187 Å / Relative weight: 1
ReflectionResolution: 1.75→32.76 Å / Num. obs: 14916 / % possible obs: 99.6 % / Redundancy: 3.7 % / Biso Wilson estimate: 17.09 Å2 / CC1/2: 0.995 / Rmerge(I) obs: 0.11 / Rpim(I) all: 0.064 / Rrim(I) all: 0.128 / Net I/σ(I): 7.4 / Num. measured all: 55881 / Scaling rejects: 17
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique allCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
1.75-1.783.70.71529467990.6270.4150.8321.899.8
9.09-32.763.30.0374111250.9940.0240.04516.596.8

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation4.42 Å28.99 Å
Translation4.42 Å28.99 Å

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Processing

Software
NameVersionClassification
PHENIXrefinement
XDSdata reduction
Aimless0.5.12data scaling
PHASER2.5.6phasing
PDB_EXTRACT3.22data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4NYX

4nyx


Resolution: 1.75→28.987 Å / SU ML: 0.18 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 19.56 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.1998 720 4.84 %Random selection
Rwork0.168 14159 --
obs0.1696 14879 99.39 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 53.97 Å2 / Biso mean: 19.4934 Å2 / Biso min: 7.22 Å2
Refinement stepCycle: final / Resolution: 1.75→28.987 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms991 0 56 185 1232
Biso mean--20.5 29.3 -
Num. residues----119
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0041115
X-RAY DIFFRACTIONf_angle_d0.9041524
X-RAY DIFFRACTIONf_chiral_restr0.047163
X-RAY DIFFRACTIONf_plane_restr0.005194
X-RAY DIFFRACTIONf_dihedral_angle_d23.661433
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 5

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.75-1.88510.26181390.22342774291399
1.8851-2.07480.25361410.190527832924100
2.0748-2.37490.20531460.16528232969100
2.3749-2.99160.21271340.1682833296799
2.9916-28.99140.16721600.1522946310699
Refinement TLS params.Method: refined / Origin x: -22.8802 Å / Origin y: 52.2464 Å / Origin z: 6.8178 Å
111213212223313233
T0.0246 Å20.0069 Å20.0072 Å2-0.0314 Å2-0.0002 Å2--0.0293 Å2
L0.3268 °20.032 °20.535 °2-0.3587 °2-0.1814 °2--0.8057 °2
S0.0414 Å °-0.0251 Å °0.0151 Å °-0.0233 Å °-0.0203 Å °-0.0023 Å °0.0887 Å °-0.003 Å °-0 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA1079 - 1197
2X-RAY DIFFRACTION1allB1
3X-RAY DIFFRACTION1allS1 - 179
4X-RAY DIFFRACTION1allC1 - 3
5X-RAY DIFFRACTION1allC4
6X-RAY DIFFRACTION1allE1

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