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- PDB-6yik: Crystal structure of the CREBBP bromodomain in complex with a tet... -

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Entry
Database: PDB / ID: 6yik
TitleCrystal structure of the CREBBP bromodomain in complex with a tetrahydroquinoxaline ligand
ComponentsCREBBP
KeywordsTRANSCRIPTION / Bromodomain / CREBBP / small molecule / benzo-diazepine / SGC / Structural Genomics Consortium
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 / 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 (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 / 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 / Regulation of FOXO transcriptional activity by acetylation / NOTCH4 Intracellular Domain Regulates Transcription / 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 / NFE2L2 regulating tumorigenic genes / peptide-lysine-N-acetyltransferase activity / FOXO-mediated transcription of cell death 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 / non-canonical NF-kappaB signal transduction / Zygotic genome activation (ZGA) / stimulatory C-type lectin receptor signaling pathway / cellular response to nutrient levels / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / acetyltransferase activity / 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) / Formation of the beta-catenin:TCF transactivating complex / Heme signaling / protein destabilization / Transcriptional activation of mitochondrial biogenesis / PPARA activates gene expression / Evasion by RSV of host interferon responses / 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 / 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 / cytoplasm / cytosol
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-OSQ / CREB-binding protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.7 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
Wellcome Trust095751/Z/11/Z United Kingdom
CitationJournal: To Be Published
Title: Crystal structure of the CREBBP bromodomain in complex with a tetrahydroquinoxaline 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,7428
Polymers42,6703
Non-polymers2,0725
Water6,936385
1
A: CREBBP
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,0523
Polymers14,2231
Non-polymers8292
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: CREBBP
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,6382
Polymers14,2231
Non-polymers4141
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: CREBBP
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,0523
Polymers14,2231
Non-polymers8292
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)80.230, 43.907, 88.270
Angle α, β, γ (deg.)90.000, 110.060, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein CREBBP


Mass: 14223.349 Da / Num. of mol.: 3
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-OSQ / (3~{R})-~{N}-[3-(3,4-dihydro-2~{H}-quinolin-1-yl)-2,2-bis(fluoranyl)propyl]-3-methyl-2-oxidanylidene-3,4-dihydro-1~{H}-quinoxaline-5-carboxamide


Mass: 414.448 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C22H24F2N4O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 385 / 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: 3.42 Å3/Da / Density % sol: 64.06 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 21% PEG3350 15% ethylene glycol 0.25M sodium formate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.97625 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Sep 13, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97625 Å / Relative weight: 1
ReflectionResolution: 1.697→48.151 Å / Num. all: 63697 / Num. obs: 63697 / % possible obs: 99 % / Redundancy: 3.4 % / Rpim(I) all: 0.03 / Rrim(I) all: 0.056 / Rsym value: 0.047 / Net I/av σ(I): 7.9 / Net I/σ(I): 14.3 / Num. measured all: 215550
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
1.7-1.793.40.4291.83011488420.2720.510.4292.996.1
1.79-1.93.40.2592.92972487940.1640.3070.2594.799
1.9-2.033.40.1594.42783282210.1010.1890.1597.399.2
2.03-2.193.40.0957.32623277580.060.1130.09511.599.6
2.19-2.43.40.06810.12433871150.0430.080.06815.699.6
2.4-2.683.40.05212.92208664630.0330.0610.05219.599.7
2.68-3.13.40.04214.61945557110.0270.050.04223.899.6
3.1-3.793.40.03615.71630948600.0230.0430.03628.499.6
3.79-5.363.30.03616.41264937990.0230.0420.03630.899.7
5.36-48.1513.20.04113681121340.0270.0490.04130.399

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation3.5 Å48.15 Å
Translation3.5 Å48.15 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: 1.7→48.15 Å / Cor.coef. Fo:Fc: 0.972 / Cor.coef. Fo:Fc free: 0.959 / SU B: 2.819 / SU ML: 0.05 / SU R Cruickshank DPI: 0.0721 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.072 / ESU R Free: 0.075
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.184 1953 3.1 %RANDOM
Rwork0.156 ---
obs0.1569 61679 99.31 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 122.9 Å2 / Biso mean: 32.625 Å2 / Biso min: 15.65 Å2
Baniso -1Baniso -2Baniso -3
1--0.59 Å20 Å20.01 Å2
2--0.35 Å20 Å2
3---0.18 Å2
Refinement stepCycle: final / Resolution: 1.7→48.15 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2848 0 180 385 3413
Biso mean--33.88 43.39 -
Num. residues----341
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0190.0133172
X-RAY DIFFRACTIONr_bond_other_d0.0010.0172858
X-RAY DIFFRACTIONr_angle_refined_deg2.3741.7214338
X-RAY DIFFRACTIONr_angle_other_deg1.5891.5846649
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4955342
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.65422.849172
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.56915518
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.3821519
X-RAY DIFFRACTIONr_chiral_restr0.1340.2366
X-RAY DIFFRACTIONr_gen_planes_refined0.0160.023408
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02673
LS refinement shellResolution: 1.7→1.744 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.25 136 -
Rwork0.239 4514 -
all-4650 -
obs--98.96 %
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)
12.4134-0.15950.07131.2976-0.06741.5706-0.05350.07730.046-0.07810.03670.1897-0.0366-0.14740.01680.0505-0.00940.01320.0368-0.0080.13957.6322-0.64481.5157
22.79461.0601-0.52931.5977-0.25080.9737-0.21480.2367-0.185-0.19220.1437-0.00640.1365-0.11720.0710.0406-0.02360.0220.1081-0.00570.048835.85737.4265-11.7834
32.42010.55650.48432.18961.11733.37350.0904-0.2294-0.01050.2852-0.04210.106-0.1599-0.1139-0.04830.16280.00240.02210.02800.03224.425311.277633.0826
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1083 - 1196
2X-RAY DIFFRACTION2B1083 - 1196
3X-RAY DIFFRACTION3C1084 - 1196

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