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- PDB-6alb: CREBBP bromodomain in complex with Cpd 30 (1-(3-(3-(1-methyl-1H-p... -

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Basic information

Entry
Database: PDB / ID: 6alb
TitleCREBBP bromodomain in complex with Cpd 30 (1-(3-(3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one)
ComponentsCREB-binding protein
KeywordsPROTEIN BINDING/INHIBITOR / CREBBP / Bromodomain / small molecule inhibitor / PROTEIN BINDING-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
CREB-binding protein/p300 RING domain / Cysteine Rich Protein / 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 ...CREB-binding protein/p300 RING domain / Cysteine Rich Protein / 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. / Zinc/RING finger domain, C3HC4 (zinc finger) / Herpes Virus-1 / Nuclear receptor coactivator, interlocking / Bromodomain-like / Histone Acetyltransferase; Chain A / Ribbon / Bromodomain, conserved site / Bromodomain signature. / Bromodomain / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily / Zinc finger, RING/FYVE/PHD-type / Up-down Bundle / 2-Layer Sandwich / Mainly Beta / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-BKJ / CREB-binding protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.053 Å
AuthorsMurray, J.M.
CitationJournal: To be published
Title: Design and Synthesis of A Biaryl Series As Inhibitors for the Bromodomains of CBP/P300
Authors: Murray, J.M.
History
DepositionAug 7, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 17, 2018Provider: repository / Type: Initial release
Revision 1.1Oct 4, 2023Group: 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

Downloads & links

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Assembly

Deposited unit
A: CREB-binding protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,4606
Polymers27,5241
Non-polymers9355
Water70339
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)92.004, 60.635, 53.835
Angle α, β, γ (deg.)90.000, 102.690, 90.000
Int Tables number5
Space group name H-MC121

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Components

#1: Protein CREB-binding protein


Mass: 27524.408 Da / Num. of mol.: 1 / Fragment: Bromodomain (UNP residue 1081-1312)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CREBBP, CBP / Production host: Escherichia coli (E. coli) / References: UniProt: Q92793, histone acetyltransferase
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-B3P / 2-[3-(2-HYDROXY-1,1-DIHYDROXYMETHYL-ETHYLAMINO)-PROPYLAMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL


Mass: 282.334 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H26N2O6 / Comment: pH buffer*YM
#4: Chemical ChemComp-BKJ / 1-{3-[3-(1-methyl-1H-pyrazol-4-yl)isoquinolin-8-yl]-1-(oxan-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl}ethan-1-one


Mass: 456.540 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H28N6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 39 / 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: 2.9 Å3/Da / Density % sol: 57.63 % / Mosaicity: 1.374 °
Crystal growTemperature: 277 K / Method: vapor diffusion / pH: 6.5 / Details: 0.2 M Li2SO4, 0.1M Bis-Tris pH 6.5, 19% PEG3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Jun 5, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.05→50 Å / Num. obs: 17377 / % possible obs: 95.8 % / Redundancy: 3.3 % / Biso Wilson estimate: 48.85 Å2 / Rmerge(I) obs: 0.097 / Rpim(I) all: 0.062 / Rrim(I) all: 0.115 / Χ2: 1.002 / Net I/σ(I): 8.2
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.05-2.122.90.4616950.8790.3110.5580.8794
2.12-2.213.10.42317300.9020.2770.5080.89695.9
2.21-2.313.30.38717390.8910.2530.4650.97696.5
2.31-2.433.20.30716220.940.2010.3691.02790.3
2.43-2.583.50.21517820.9720.1330.2540.98998.8
2.58-2.783.50.16617850.9780.1030.1960.97398.3
2.78-3.063.50.11617740.9840.0720.1370.96797.8
3.06-3.513.30.09717030.980.0620.1161.05694.3
3.51-4.423.50.08517920.9850.0530.11.02198.2
4.42-503.40.08717550.9850.0560.1041.20794

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Processing

Software
NameVersionClassification
DENZOdata reduction
SCALEPACKdata scaling
PHENIXdev_2747refinement
PDB_EXTRACT3.22data extraction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5I8G

5i8g


Resolution: 2.053→34.262 Å / SU ML: 0.29 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 33.62
RfactorNum. reflection% reflection
Rfree0.2425 900 5.18 %
Rwork0.2212 --
obs0.2224 17373 95.53 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 145.42 Å2 / Biso mean: 66.3373 Å2 / Biso min: 33.05 Å2
Refinement stepCycle: final / Resolution: 2.053→34.262 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1758 0 56 39 1853
Biso mean--67.24 55.28 -
Num. residues----212
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0081864
X-RAY DIFFRACTIONf_angle_d1.2762527
X-RAY DIFFRACTIONf_chiral_restr0.152255
X-RAY DIFFRACTIONf_plane_restr0.006322
X-RAY DIFFRACTIONf_dihedral_angle_d20.1121114
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 6

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.0528-2.18140.37161490.34442634278393
2.1814-2.34980.291330.28142766289997
2.3498-2.58620.26941460.23812708285494
2.5862-2.96020.27631690.24532782295198
2.9602-3.72890.28391400.23472783292396
3.7289-34.26710.20351630.19182800296396
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)
10.72010.7899-0.17790.8864-0.04040.37690.0357-0.04210.0117-0.0817-0.09910.06530.07820.004-00.36960.0251-0.00160.36740.01880.382416.777-2.8888.757
20.01410.0057-0.00730.00310.0033-0.00490.0324-0.0326-0.03870.00120.1114-0.0295-0.0813-0.106600.565-0.04960.19250.4268-0.06030.616131.95313.03613.618
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN A AND ( RESID 1080:1312 OR RESID 1401:1403 ) )A1080 - 1312
2X-RAY DIFFRACTION1( CHAIN A AND ( RESID 1080:1312 OR RESID 1401:1403 ) )A1401 - 1403
3X-RAY DIFFRACTION2( CHAIN A AND RESID 1405:1405 )A1405

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