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- PDB-6yij: Crystal structure of the CREBBP bromodomain in complex with a ben... -

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Basic information

Entry
Database: PDB / ID: 6yij
TitleCrystal structure of the CREBBP bromodomain in complex with a benzo-diazepine ligand
ComponentsCREBBPCREB-binding protein
KeywordsTRANSCRIPTION / Bromodomain / CREBBP / small molecule / benzo-diazepine / SGC / Structural Genomics Consortium
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
Chem-OSN / CREB-binding protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.2 Å
AuthorsPicaud, S. / Brand, M. / Tobias, K. / von Delft, F. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C. / Conway, S. / Filippakopoulos, P.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom)MR/N010051/1 United Kingdom
CitationJournal: To Be Published
Title: Crystal structure of the CREBBP bromodomain in complex with a benzo-diazepine ligand
Authors: Picaud, S. / Brand, M. / Tobias, K. / von Delft, F. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C. / Conway, S. / Filippakopoulos, P.
History
DepositionApr 1, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 15, 2020Provider: repository / Type: Initial release
Revision 1.1Jan 24, 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: CREBBP
B: CREBBP
C: CREBBP
D: CREBBP
E: CREBBP
F: CREBBP
G: CREBBP
hetero molecules


Theoretical massNumber of molelcules
Total (without water)102,40214
Polymers99,5637
Non-polymers2,8397
Water4,035224
1
A: CREBBP
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,6292
Polymers14,2231
Non-polymers4061
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: CREBBP
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,6292
Polymers14,2231
Non-polymers4061
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: CREBBP
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,6292
Polymers14,2231
Non-polymers4061
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: CREBBP
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,6292
Polymers14,2231
Non-polymers4061
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
5
E: CREBBP
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,6292
Polymers14,2231
Non-polymers4061
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
6
F: CREBBP
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,6292
Polymers14,2231
Non-polymers4061
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
7
G: CREBBP
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,6292
Polymers14,2231
Non-polymers4061
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)96.694, 96.694, 251.713
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number96
Space group name H-MP43212

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Components

#1: Protein
CREBBP / CREB-binding protein


Mass: 14223.349 Da / Num. of mol.: 7
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Plasmid: pNIC28-Bsa4 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: Q92793, histone acetyltransferase, Transferases; Acyltransferases; Transferring groups other than aminoacyl groups
#2: Chemical
ChemComp-OSN / (4~{R})-6-[(~{E})-5-(7-methoxy-3,4-dihydro-2~{H}-quinolin-1-yl)pent-1-enyl]-4-methyl-1,3,4,5-tetrahydro-1,5-benzodiazepin-2-one


Mass: 405.533 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C25H31N3O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 224 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.95 Å3/Da / Density % sol: 58.37 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8.3
Details: 20% ethylene glycol 21% PEG6K 0.1M tris pH 8.3 0.125M lithium chloride

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.9763 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Sep 25, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 2.2→47.5 Å / Num. obs: 61638 / % possible obs: 100 % / Redundancy: 12.7 % / Rpim(I) all: 0.047 / Rrim(I) all: 0.167 / Rsym value: 0.16 / Net I/av σ(I): 3.9 / Net I/σ(I): 11.1
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique obsRpim(I) allRrim(I) allRsym valueNet I/σ(I) obs% possible all
2.2-2.3212.61.4380.511117288230.421.4991.4382100
2.32-2.4613.30.9760.811135383800.2771.0150.9762.9100
2.46-2.6312.80.661.210131378960.1910.6870.664.1100
2.63-2.8413.20.4421.79788873900.1260.460.4425.9100
2.84-3.1113.30.2732.89074167980.0770.2840.2739.1100
3.11-3.4812.70.1734.37852261940.0510.180.17313.9100
3.48-4.0212.20.1016.76713955160.030.1060.10122.5100
4.02-4.9212.20.0738.35729047010.0220.0770.07328.1100
4.92-6.9611.70.0718.24371937370.0220.0740.07125100
6.96-47.47911.40.0478.62513522030.0150.050.04731.899.7

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation3.5 Å47.48 Å
Translation3.5 Å47.48 Å

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Processing

Software
NameVersionClassification
REFMAC5.8.0258refinement
SCALA3.3.22data scaling
PHASER2.5.7phasing
PDB_EXTRACT3.25data extraction
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3DWY

3dwy


Resolution: 2.2→47.5 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.916 / SU B: 13.746 / SU ML: 0.179 / SU R Cruickshank DPI: 0.2173 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.217 / ESU R Free: 0.208
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2693 2003 3.3 %RANDOM
Rwork0.2022 ---
obs0.2044 59475 99.88 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 177.83 Å2 / Biso mean: 44.856 Å2 / Biso min: 19.53 Å2
Baniso -1Baniso -2Baniso -3
1-0.45 Å20 Å2-0 Å2
2--0.45 Å2-0 Å2
3----0.89 Å2
Refinement stepCycle: final / Resolution: 2.2→47.5 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6732 0 210 224 7166
Biso mean--42.09 38.44 -
Num. residues----813
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0137164
X-RAY DIFFRACTIONr_bond_other_d0.0010.0176556
X-RAY DIFFRACTIONr_angle_refined_deg2.1711.6919738
X-RAY DIFFRACTIONr_angle_other_deg1.451.58515256
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.0885808
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.46722.85386
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.689151203
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.6641543
X-RAY DIFFRACTIONr_chiral_restr0.1040.2855
X-RAY DIFFRACTIONr_gen_planes_refined0.0130.027723
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021494
LS refinement shellResolution: 2.2→2.257 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.351 141 -
Rwork0.281 4284 -
all-4425 -
obs--99.8 %
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)
10.4309-0.51510.28990.9464-0.60950.9067-0.0256-0.01950.07520.0119-0.007-0.0438-0.08420.06330.03260.12080.0131-0.00230.09890.00580.02220.434838.368894.8717
21.20550.2695-0.50250.1417-0.34450.91220.01020.0486-0.07480.0248-0.0213-0.0113-0.02960.11110.01110.0752-0.00260.0120.0711-0.01820.078-8.851427.07784.7889
32.3051-0.0417-0.29040.52020.62550.90280.03770.1532-0.0685-0.04590.0419-0.0258-0.12670.1205-0.07960.0545-0.03840.01960.1183-0.00650.0649-6.448323.495148.895
40.79920.11640.20970.77870.04211.8210.05730.05830.0599-0.0142-0.05760.03460.1431-0.23620.00030.0712-0.04780.00250.1441-0.01530.010512.177966.723867.9558
50.87070.3741-0.32720.4703-0.35621.90780.0230.0020.1056-0.02580.01730.0179-0.1605-0.1176-0.04030.0639-0.00350.00250.0765-0.00390.067718.826337.276457.9432
60.918-0.12370.66640.5112-0.49650.82160.04030.01840.0593-0.0068-0.1038-0.03340.04390.11730.06350.07850.0476-0.01110.19980.0040.007838.173220.761784.1029
71.1104-0.57450.70410.3165-0.43991.7725-0.0102-0.06310.0510.01260.02330.00320.07870.1953-0.01310.04820.01680.00770.12110.01420.060137.600720.037948.309
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1079 - 1197
2X-RAY DIFFRACTION2B1079 - 1197
3X-RAY DIFFRACTION3C1080 - 1197
4X-RAY DIFFRACTION4D1084 - 1196
5X-RAY DIFFRACTION5E1084 - 1197
6X-RAY DIFFRACTION6F1079 - 1196
7X-RAY DIFFRACTION7G1085 - 1196

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