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- PDB-4nr4: Crystal structure of the bromodomain of human CREBBP in complex w... -

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Basic information

Entry
Database: PDB / ID: 4nr4
TitleCrystal structure of the bromodomain of human CREBBP in complex with an isoxazolyl-benzimidazole ligand
ComponentsCREB-binding protein
KeywordsTRANSCRIPTION/INHIBITOR / Structural Genomics Consortium / SGC / chemical tool / small molecule inhibitor / transcription / TRANSCRIPTION-INHIBITOR complex
Function / homology
Function and homology information


peptide lactyltransferase (CoA-dependent) activity / regulation of smoothened signaling pathway / 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 / 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 / regulation of smoothened signaling pathway / 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 / 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 / FOXO-mediated transcription of cell death genes / Regulation of NFE2L2 gene expression / negative regulation of transcription by RNA polymerase I / NOTCH3 Intracellular Domain Regulates Transcription / TRAF6 mediated IRF7 activation / NFE2L2 regulating anti-oxidant/detoxification enzymes / peptide-lysine-N-acetyltransferase activity / NFE2L2 regulating tumorigenic 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 / 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 / positive regulation of double-strand break repair via homologous recombination / Attenuation phase / 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 / Transferases; Acyltransferases; Transferring groups other than aminoacyl groups / RORA activates gene expression / 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) / protein destabilization / Formation of the beta-catenin:TCF transactivating complex / Heme signaling / 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 / rhythmic process / p53 binding / Circadian Clock / TRAF3-dependent IRF activation pathway / HATs acetylate histones / protein-containing complex assembly / DNA-binding transcription factor binding / RNA polymerase II-specific DNA-binding transcription factor binding / Estrogen-dependent gene expression / 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 / 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-2LK / CREB-binding protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.69 Å
AuthorsFilippakopoulos, P. / Picaud, S. / Felletar, I. / Hay, D. / Fedorov, O. / Martin, S. / von Delft, F. / Brennan, P. / Arrowsmith, C.H. / Edwards, A.M. ...Filippakopoulos, P. / Picaud, S. / Felletar, I. / Hay, D. / Fedorov, O. / Martin, S. / 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 an isoxazolyl-benzimidazole ligand
Authors: Filippakopoulos, P. / Picaud, S. / Felletar, I. / Hay, D. / Fedorov, O. / Martin, S. / von Delft, F. / Brennan, P. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C. / Knapp, S.
History
DepositionNov 26, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 18, 2013Provider: 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 / pdbx_struct_conn_angle / struct_conn / 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 / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr2_auth_seq_id / _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
B: CREB-binding protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)29,6098
Polymers28,4472
Non-polymers1,1626
Water5,152286
1
A: CREB-binding protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,6233
Polymers14,2231
Non-polymers4002
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: CREB-binding protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,9855
Polymers14,2231
Non-polymers7624
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)52.870, 57.110, 82.840
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.: 2 / 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, histone acetyltransferase
#2: Chemical ChemComp-2LK / 1-(4-chlorobenzyl)-5-(3,5-dimethyl-1,2-oxazol-4-yl)-1H-benzimidazole


Mass: 337.803 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C19H16ClN3O
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 286 / 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: 2.2 Å3/Da / Density % sol: 44.04 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8
Details: 0.1M MgCl, 0.1M Tris pH 8.0, 20% PEG 6K, 10% EtGly, VAPOR DIFFUSION, SITTING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.54178 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Oct 11, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionRedundancy: 3.8 % / Av σ(I) over netI: 7.8 / Number: 108377 / Rsym value: 0.046 / D res high: 1.69 Å / D res low: 25.125 Å / Num. obs: 28319 / % possible obs: 98.5
Diffraction reflection shell
Highest resolution (Å)Lowest resolution (Å)% possible obs (%)IDRmerge(I) obsRsym valueRedundancy
5.3425.1299.110.0390.0393.5
3.785.3410010.0350.0353.8
3.093.7899.910.0350.0353.9
2.673.0999.810.0410.0413.9
2.392.6799.310.0450.0453.9
2.182.399910.0520.0523.9
2.022.1898.810.0630.0633.9
1.892.0298.310.080.083.8
1.781.8997.210.0970.0973.8
1.691.7896.610.1310.1313.7
ReflectionResolution: 1.69→26.43 Å / Num. all: 28750 / Num. obs: 28319 / % possible obs: 98.5 % / Redundancy: 3.8 % / Biso Wilson estimate: 15.6 Å2 / Rmerge(I) obs: 0.046 / Rsym value: 0.046 / Net I/σ(I): 18
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRsym value% possible all
1.69-1.783.70.1315.41484639760.13196.6
1.78-1.893.80.0977.41448938110.09797.2
1.89-2.023.80.088.31382135970.0898.3
2.02-2.183.90.06310.31317034060.06398.8
2.18-2.393.90.05212.21224331510.05299
2.39-2.673.90.04513.91117228630.04599.3
2.67-3.093.90.04114.7997825590.04199.8
3.09-3.783.90.03515.4854822050.03599.9
3.78-5.343.80.03510.4655717330.035100
5.34-26.433.50.0398.4355310180.03999.1

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Phasing

PhasingMethod: molecular replacement
Phasing MRRfactor: 55.83 / Model details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation3.5 Å25.12 Å
Translation3.5 Å25.12 Å

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Processing

Software
NameVersionClassificationNB
SCALA3.3.16data scaling
PHASER2.1.4phasing
REFMACrefinement
PDB_EXTRACT3.11data extraction
CrystalCleardata collection
MOSFLMdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 3DWY

3dwy


Resolution: 1.69→26.43 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.945 / WRfactor Rfree: 0.1926 / WRfactor Rwork: 0.1554 / Occupancy max: 1 / Occupancy min: 0.5 / FOM work R set: 0.9028 / SU B: 2.57 / SU ML: 0.049 / SU R Cruickshank DPI: 0.0947 / SU Rfree: 0.0958 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.095 / ESU R Free: 0.096 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES: WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.1916 1433 5.1 %RANDOM
Rwork0.1546 ---
all0.1564 28774 --
obs0.1564 28265 98.23 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 88.94 Å2 / Biso mean: 15.9884 Å2 / Biso min: 5.79 Å2
Baniso -1Baniso -2Baniso -3
1-0.27 Å20 Å20 Å2
2---0.47 Å20 Å2
3---0.2 Å2
Refinement stepCycle: LAST / Resolution: 1.69→26.43 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1852 0 81 286 2219
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0222014
X-RAY DIFFRACTIONr_bond_other_d0.0010.021372
X-RAY DIFFRACTIONr_angle_refined_deg1.5782.0312747
X-RAY DIFFRACTIONr_angle_other_deg0.9333.0063337
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.1135227
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.27424.73795
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.09215329
X-RAY DIFFRACTIONr_dihedral_angle_4_deg9.2221511
X-RAY DIFFRACTIONr_chiral_restr0.0890.2279
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0212196
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02402
LS refinement shellResolution: 1.69→1.734 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.24 98 -
Rwork0.187 1770 -
all-1868 -
obs--95.65 %
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)
16.04522.49520.85344.65042.4681.35690.1269-0.09630.1378-0.1592-0.0799-0.0572-0.1053-0.038-0.0470.0453-0.01690.01650.0285-0.00320.017618.695170.168925.2587
20.1440.0607-0.06960.27-0.08690.2083-0.00660.00080.01640.0108-0.00940.01360.0210.01990.01610.03410.00050.0010.03450.00160.028116.432351.235720.875
30.10270.4672-0.12982.599-0.25990.44140.01580.01690.01940.0624-0.01510.1147-0.0087-0.0421-0.00070.0130.01040.00170.0650.00580.03686.701857.173117.2394
43.5004-4.89120.16898.24961.00251.09390.10410.09230.1342-0.0350.0523-0.34580.12640.1773-0.15650.0590.0207-0.01660.0301-0.02110.071314.769319.595836.4666
50.20460.14850.00930.33110.0740.40790.0026-0.0016-0.014-0.0073-0.0026-0.02890.0031-0.017200.025-0.0022-0.00060.03060.00210.03212.910936.001241.8212
60.0159-0.16640.1886.77880.61923.66730.0167-0.00220.00130.14510.0538-0.0460.3747-0.0421-0.07050.0745-0.0296-0.01370.02780.02360.04866.529118.991544.1869
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1085 - 1095
2X-RAY DIFFRACTION2A1096 - 1169
3X-RAY DIFFRACTION3A1170 - 1197
4X-RAY DIFFRACTION4B1086 - 1099
5X-RAY DIFFRACTION5B1100 - 1184
6X-RAY DIFFRACTION6B1185 - 1197

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