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

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Basic information

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


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 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 / peptide-lysine-N-acetyltransferase activity / FOXO-mediated transcription of cell death genes / NFE2L2 regulating tumorigenic genes / embryonic digit morphogenesis / homeostatic process / Notch-HLH transcription pathway / protein acetylation / 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 / cellular response to nutrient levels / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / 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 / protein destabilization / Heme signaling / Transcriptional activation of mitochondrial biogenesis / transcription coactivator binding / PPARA activates gene expression / Cytoprotection by HMOX1 / NOTCH1 Intracellular Domain Regulates Transcription / chromatin DNA binding / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / Pre-NOTCH Transcription and Translation / 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 / transcription regulator complex / RNA polymerase II-specific DNA-binding transcription factor binding / damaged DNA binding / transcription coactivator activity / response to hypoxia / nuclear body / 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. / Coactivator CBP, KIX domain superfamily / Histone acetyltransferase Rtt109/CBP / 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
6-bromo-3-methyl-3,4-dihydroquinazolin-2(1H)-one / CREB-binding protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.83 Å
AuthorsFilippakopoulos, P. / Picaud, S. / Felletar, I. / Fedorov, O. / Martin, S. / Monteiro, O.P. / von Delft, F. / Brennan, P. / Arrowsmith, C.H. / Edwards, A.M. ...Filippakopoulos, P. / Picaud, S. / Felletar, I. / Fedorov, O. / Martin, S. / Monteiro, O.P. / 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 quinazolin-one ligand
Authors: Filippakopoulos, P. / Picaud, S. / Felletar, I. / Fedorov, O. / Martin, S. / Monteiro, O.P. / 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
B: CREB-binding protein
C: CREB-binding protein
D: CREB-binding protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,8588
Polymers56,8934
Non-polymers9644
Water4,720262
1
A: CREB-binding protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,4642
Polymers14,2231
Non-polymers2411
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: CREB-binding protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,4642
Polymers14,2231
Non-polymers2411
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: CREB-binding protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,4642
Polymers14,2231
Non-polymers2411
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: CREB-binding protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,4642
Polymers14,2231
Non-polymers2411
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)36.150, 55.680, 69.080
Angle α, β, γ (deg.)90.210, 104.030, 108.610
Int Tables number1
Space group name H-MP1

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Components

#1: Protein
CREB-binding protein /


Mass: 14223.349 Da / Num. of mol.: 4 / 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-15E / 6-bromo-3-methyl-3,4-dihydroquinazolin-2(1H)-one


Mass: 241.085 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C9H9BrN2O
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 262 / 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: 2.24 Å3/Da / Density % sol: 45.05 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 0.15M KSCN, 25% PEG_3350, 5% ethylene glycol, pH 7.5, 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: 1.52 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Apr 15, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.52 Å / Relative weight: 1
ReflectionRedundancy: 2.4 % / Av σ(I) over netI: 9.4 / Number: 96948 / Rsym value: 0.053 / D res high: 1.83 Å / D res low: 27.117 Å / Num. obs: 40271 / % possible obs: 92.5
Diffraction reflection shell
Highest resolution (Å)Lowest resolution (Å)% possible obs (%)IDRmerge(I) obsRsym valueRedundancy
5.7927.1296.610.0370.0372.4
4.095.7996.710.0310.0312.4
3.344.0995.810.0330.0332.4
2.893.3494.910.0440.0442.4
2.592.8993.910.0550.0552.4
2.362.5993.210.0710.0712.4
2.192.369210.10.12.4
2.052.1990.910.1420.1422.4
1.932.0590.210.2440.2442.4
1.831.9389.210.3990.3992.4
ReflectionResolution: 1.83→27.27 Å / Num. all: 43536 / Num. obs: 40271 / % possible obs: 92.5 % / Redundancy: 2.4 % / Biso Wilson estimate: 26.5 Å2 / Rmerge(I) obs: 0.053 / Rsym value: 0.053 / Net I/σ(I): 10.1
Reflection shell

Diffraction-ID: 1 / Redundancy: 2.4 %

Resolution (Å)Rmerge(I) obsMean I/σ(I) obsNum. unique allRsym value% possible all
1.83-1.930.399254910.39992.5
1.93-2.050.2443.251960.24493.1
2.05-2.190.1425.549380.14293.6
2.19-2.360.17.446460.194.2
2.36-2.590.0719.843490.07194.8
2.59-2.890.05512.639540.05595.3
2.89-3.340.04417.135010.04495.8
3.34-4.090.03322.830010.03396.3
4.09-5.790.03123.523110.03196.6
5.79-27.270.03720.912450.03796.6

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Phasing

PhasingMethod: molecular replacement
Phasing MRRfactor: 49.75 / Model details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation3.5 Å27.12 Å
Translation3.5 Å27.12 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: Ensemble of PDB entries 3DAI, 3HMH, 2GRC, 2OO1, 2OSS, 2OUO, 3D7C, and 3DWY

3dai

3hmh

2grc

2oo1

2oss

2ouo

3d7c

3dwy


Resolution: 1.83→27.27 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.928 / WRfactor Rfree: 0.2479 / WRfactor Rwork: 0.1897 / Occupancy max: 1 / Occupancy min: 0.5 / FOM work R set: 0.829 / SU B: 6.934 / SU ML: 0.109 / SU R Cruickshank DPI: 0.1611 / SU Rfree: 0.1582 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.161 / ESU R Free: 0.158 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.251 1859 4.6 %RANDOM
Rwork0.1918 ---
obs0.1946 40265 92.5 %-
all-43530 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 114.17 Å2 / Biso mean: 27.8258 Å2 / Biso min: 11.17 Å2
Baniso -1Baniso -2Baniso -3
1-1.34 Å2-0.35 Å2-0.64 Å2
2---1.4 Å2-0.35 Å2
3----0.48 Å2
Refinement stepCycle: LAST / Resolution: 1.83→27.27 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3804 0 52 262 4118
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0224045
X-RAY DIFFRACTIONr_bond_other_d0.0010.022812
X-RAY DIFFRACTIONr_angle_refined_deg1.4971.9885512
X-RAY DIFFRACTIONr_angle_other_deg0.9573.0016824
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.6665457
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.38424.619210
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.94615694
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.1171526
X-RAY DIFFRACTIONr_chiral_restr0.0960.2578
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0214406
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02804
LS refinement shellResolution: 1.83→1.877 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.453 137 -
Rwork0.378 2714 -
all-2851 -
obs--88.84 %
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)
10.30940.19830.18970.32950.0410.97550.0426-0.0189-0.00970.05740.01330.0213-0.02190.0113-0.05590.0443-0.00040.00430.0192-0.01020.02967.14253.290876.7097
20.6362-0.0199-0.39020.0657-0.22041.07320.03070.07790.0043-0.0006-0.0010.0086-0.0076-0.0399-0.02970.06480.0202-0.01480.0274-0.00610.03354.164454.055862.1324
32.31931.30984.04772.84222.49897.191-0.11490.11440.06870.05630.06350.0337-0.34140.17430.05130.20090.01770.10030.02630.01110.069611.692566.975373.3421
40.9539-0.0234-0.22950.2812-0.40911.66190.16320.0229-0.0551-0.2087-0.05180.10320.2519-0.1371-0.11150.18160.0412-0.07520.0517-0.02750.06293.908929.546380.0186
50.0559-0.1351-0.12171.0596-0.14660.56850.0164-0.0094-0.0012-0.0391-0.03140.0394-0.00610.02750.01490.0245-0.01550.01620.0404-0.01260.04697.45539.32986.4206
60.9564-0.9491-1.1231.56870.81611.98780.0722-0.04180.0055-0.02340.08680.05650.1816-0.0794-0.15910.1652-0.0652-0.04890.03670.00930.08064.635827.481892.4589
74.74210.85064.15950.26180.93724.5892-0.0219-0.32060.06840.0213-0.04590.0595-0.3028-0.27430.06780.18220.01050.05050.0339-0.01410.05134.890737.962148.5642
80.10910.03230.11670.64960.24510.90570.06720.0098-0.00630.0132-0.01830.04230.0330.0425-0.04890.04410.00530.00490.0378-0.00980.04145.235626.670539.1956
90.8220.65061.49240.72751.21373.18840.04480.12330.02130.02470.08260.0341-0.12850.1246-0.12740.10120.04820.06230.04690.02960.08643.264238.15633.6583
100.3332-0.2119-0.32340.3588-0.10770.81020.05340.0063-0.0142-0.0758-0.0040.07920.0281-0.0076-0.04940.0421-0.0014-0.00490.02130.00080.0437-13.148765.353948.8026
110.369-0.3489-0.37550.8166-0.07710.87680.0321-0.0584-0.0024-0.09130.01070.02720.09160.0817-0.04280.06370.0027-0.00850.03980.00490.0283-5.49563.892153.7344
121.5988-1.3068-1.61971.65091.18942.21570.1153-0.0976-0.0622-0.01190.01550.12180.15540.0575-0.13090.1876-0.0331-0.07680.03140.02660.0822-11.52756.41658.1318
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1081 - 1157
2X-RAY DIFFRACTION2A1158 - 1182
3X-RAY DIFFRACTION3A1183 - 1196
4X-RAY DIFFRACTION4B1082 - 1114
5X-RAY DIFFRACTION5B1115 - 1168
6X-RAY DIFFRACTION6B1169 - 1196
7X-RAY DIFFRACTION7C1083 - 1108
8X-RAY DIFFRACTION8C1109 - 1168
9X-RAY DIFFRACTION9C1169 - 1196
10X-RAY DIFFRACTION10D1083 - 1147
11X-RAY DIFFRACTION11D1148 - 1168
12X-RAY DIFFRACTION12D1169 - 1196

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