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- PDB-8fv2: Bromodomain of CBP liganded with CCS-1477 -

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Basic information

Entry
Database: PDB / ID: 8fv2
TitleBromodomain of CBP liganded with CCS-1477
ComponentsCREB-binding protein
KeywordsTRANSCRIPTION/INHIBITOR / bromodomain / small molecule ligand / complex / TRANSCRIPTION / TRANSCRIPTION-INHIBITOR complex
Function / homology
Function and homology information


peptide lactyltransferase (CoA-dependent) activity / NFE2L2 regulating ER-stress associated genes / 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 / regulation of smoothened signaling pathway ...peptide lactyltransferase (CoA-dependent) activity / NFE2L2 regulating ER-stress associated genes / 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 / regulation of smoothened signaling pathway / 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 / Regulation of FOXO transcriptional activity by acetylation / RUNX3 regulates NOTCH signaling / NOTCH4 Intracellular Domain Regulates Transcription / Nuclear events mediated by NFE2L2 / Regulation of NFE2L2 gene expression / Regulation of gene expression by Hypoxia-inducible Factor / NOTCH3 Intracellular Domain Regulates Transcription / negative regulation of transcription by RNA polymerase I / TRAF6 mediated IRF7 activation / NFE2L2 regulating tumorigenic genes / NFE2L2 regulating anti-oxidant/detoxification enzymes / embryonic digit morphogenesis / protein-lysine-acetyltransferase activity / protein acetylation / homeostatic process / Notch-HLH transcription pathway / Formation of paraxial mesoderm / positive regulation of transforming growth factor beta receptor signaling pathway / acetyltransferase activity / FOXO-mediated transcription of cell death genes / stimulatory C-type lectin receptor signaling pathway / Zygotic genome activation (ZGA) / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / histone acetyltransferase complex / canonical NF-kappaB signal transduction / Attenuation phase / histone acetyltransferase activity / cellular response to nutrient levels / positive regulation of double-strand break repair via homologous recombination / histone acetyltransferase / regulation of cellular response to heat / : / NPAS4 regulates expression of target genes / Regulation of lipid metabolism by PPARalpha / Transferases; Acyltransferases; Transferring groups other than aminoacyl groups / Transcriptional and post-translational regulation of MITF-M expression and activity / CD209 (DC-SIGN) signaling / BMAL1:CLOCK,NPAS2 activates circadian expression / SUMOylation of transcription cofactors / Activation of gene expression by SREBF (SREBP) / Heme signaling / Transcriptional activation of mitochondrial biogenesis / Formation of the beta-catenin:TCF transactivating complex / PPARA activates gene expression / Cytoprotection by HMOX1 / protein destabilization / Evasion by RSV of host interferon responses / chromatin DNA binding / NOTCH1 Intracellular Domain Regulates Transcription / Transcriptional regulation of white adipocyte differentiation / positive regulation of protein localization to nucleus / Pre-NOTCH Transcription and Translation / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / tau protein binding / transcription coactivator binding / Activation of anterior HOX genes in hindbrain development during early embryogenesis / cellular response to UV / p53 binding / : / rhythmic process / transcription corepressor activity / HATs acetylate histones / MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis / TRAF3-dependent IRF activation pathway / protein-containing complex assembly / transcription regulator complex / DNA-binding transcription factor binding / Estrogen-dependent gene expression / damaged DNA binding / RNA polymerase II-specific DNA-binding transcription factor binding / transcription coactivator activity / response to hypoxia / nuclear body / chromatin binding / regulation of DNA-templated transcription / chromatin / positive regulation of DNA-templated transcription / SARS-CoV-2 activates/modulates innate and adaptive immune responses / negative regulation of transcription by RNA polymerase II / signal transduction / positive regulation of transcription by RNA polymerase II / zinc ion binding / nucleoplasm / nucleus / 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 / : / Histone acetyltransferase p300-like, PHD 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 / : / Histone acetyltransferase p300-like, PHD domain / 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, conserved site / Bromodomain signature. / Bromodomain / bromo domain / Bromodomain / Bromodomain (BrD) profile. / Bromodomain-like superfamily / Zinc finger, RING/FYVE/PHD-type
Similarity search - Domain/homology
Chem-JHL / PHOSPHATE ION / CREB-binding protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.87 Å
AuthorsSchonbrunn, E. / Bikowitz, M.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Commun / Year: 2024
Title: Group 3 medulloblastoma transcriptional networks collapse under domain specific EP300/CBP inhibition.
Authors: Shendy, N.A.M. / Bikowitz, M. / Sigua, L.H. / Zhang, Y. / Mercier, A. / Khashana, Y. / Nance, S. / Liu, Q. / Delahunty, I.M. / Robinson, S. / Goel, V. / Rees, M.G. / Ronan, M.A. / Wang, T. / ...Authors: Shendy, N.A.M. / Bikowitz, M. / Sigua, L.H. / Zhang, Y. / Mercier, A. / Khashana, Y. / Nance, S. / Liu, Q. / Delahunty, I.M. / Robinson, S. / Goel, V. / Rees, M.G. / Ronan, M.A. / Wang, T. / Kocak, M. / Roth, J.A. / Wang, Y. / Freeman, B.B. / Orr, B.A. / Abraham, B.J. / Roussel, M.F. / Schonbrunn, E. / Qi, J. / Durbin, A.D.
History
DepositionJan 18, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 7, 2024Provider: repository / Type: Initial release
Revision 1.1Jun 5, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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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)59,19817
Polymers55,3924
Non-polymers3,80713
Water8,341463
1
A: CREB-binding protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,6675
Polymers13,8481
Non-polymers8204
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: CREB-binding protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,1696
Polymers13,8481
Non-polymers1,3215
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: CREB-binding protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,9173
Polymers13,8481
Non-polymers1,0692
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: CREB-binding protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,4453
Polymers13,8481
Non-polymers5972
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)79.453, 79.453, 97.127
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number76
Space group name H-MP41

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Components

#1: Protein
CREB-binding protein / Histone lysine acetyltransferase CREBBP / Protein-lysine acetyltransferase CREBBP


Mass: 13847.882 Da / Num. of mol.: 4 / Fragment: bromodomain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CREBBP, CBP / Plasmid: pNIC28-Bsa4 / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): RIL
References: UniProt: Q92793, histone acetyltransferase, Transferases; Acyltransferases; Transferring groups other than aminoacyl groups
#2: Chemical
ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: PO4
#3: Chemical
ChemComp-JHL / (6S)-1-[3,4-bis(fluoranyl)phenyl]-6-[5-(3,5-dimethyl-1,2-oxazol-4-yl)-1-(4-methoxycyclohexyl)benzimidazol-2-yl]piperidin-2-one / CCS1477 / Inobrodib


Mass: 534.597 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C30H32F2N4O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 463 / 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: 2.77 Å3/Da / Density % sol: 55.55 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.2
Details: 0.056M Sodium phosphate monobasic monohydrate, 1.344M Potassium phosphate dibasic

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Data collection

DiffractionMean temperature: 93 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 / Wavelength: 1.54178 Å
DetectorType: RIGAKU SATURN 944+ / Detector: CCD / Date: Feb 7, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 1.87→41.44 Å / Num. obs: 49406 / % possible obs: 99.1 % / Redundancy: 4 % / Biso Wilson estimate: 17.8 Å2 / CC1/2: 0.985 / Rrim(I) all: 0.155 / Net I/σ(I): 9.9
Reflection shellResolution: 1.87→1.9 Å / Redundancy: 2.4 % / Mean I/σ(I) obs: 0.8 / Num. unique obs: 2111 / CC1/2: 0.535 / Rrim(I) all: 0.966 / % possible all: 84

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Processing

Software
NameVersionClassification
PHENIX1.20.1-4487refinement
HKL-2000719.2data reduction
HKL-2000719.2data scaling
PHENIX1.20.1-4487phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.87→41.44 Å / SU ML: 0.25 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 21.68 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2259 1489 3.02 %
Rwork0.1897 --
obs0.1908 49333 99.28 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.87→41.44 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3863 0 267 463 4593
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.008
X-RAY DIFFRACTIONf_angle_d1.11
X-RAY DIFFRACTIONf_dihedral_angle_d18.081571
X-RAY DIFFRACTIONf_chiral_restr0.058594
X-RAY DIFFRACTIONf_plane_restr0.008748
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.87-1.930.32321240.34284061X-RAY DIFFRACTION93
1.93-20.27011330.25334332X-RAY DIFFRACTION100
2-2.080.23551380.21634373X-RAY DIFFRACTION100
2.08-2.180.25531360.19694350X-RAY DIFFRACTION100
2.18-2.290.23551350.20214391X-RAY DIFFRACTION100
2.29-2.430.27761360.20284371X-RAY DIFFRACTION100
2.43-2.620.22981360.19244357X-RAY DIFFRACTION100
2.62-2.890.2581340.18854364X-RAY DIFFRACTION100
2.89-3.30.24561410.18114419X-RAY DIFFRACTION100
3.3-4.160.20151340.15794392X-RAY DIFFRACTION100
4.16-41.440.15811420.16864434X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: -5.3816 Å / Origin y: -34.3711 Å / Origin z: 18.4264 Å
111213212223313233
T0.1586 Å20.0036 Å2-0.0021 Å2-0.1595 Å2-0.0007 Å2--0.1854 Å2
L0.021 °20.0323 °2-0.0376 °2-0.0103 °2-0.0334 °2--0.1513 °2
S0.0005 Å °-0.0199 Å °-0.0064 Å °-0.0146 Å °-0.0002 Å °-0.0041 Å °0.0084 Å °0.0067 Å °0.0008 Å °
Refinement TLS groupSelection details: all

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