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- PDB-8ga2: Bromodomain of CBP liganded with inhibitor iCBP5 -

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Basic information

Entry
Database: PDB / ID: 8ga2
TitleBromodomain of CBP liganded with inhibitor iCBP5
ComponentsCREB-binding protein
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / bromodomain / complex / TRANSCRIPTION / TRANSFERASE-TRANSFERASE 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
: / CREB-binding protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.85 Å
AuthorsSchonbrunn, E. / Bikowitz, M.
Funding support United States, 1items
OrganizationGrant numberCountry
Not funded United States
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
DepositionFeb 22, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 28, 2024Provider: repository / Type: Initial release
Revision 1.1May 8, 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
D: CREB-binding protein
C: CREB-binding protein
B: CREB-binding protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,4489
Polymers55,3924
Non-polymers2,0575
Water3,423190
1
A: CREB-binding protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,4093
Polymers13,8481
Non-polymers5612
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
D: CREB-binding protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,3462
Polymers13,8481
Non-polymers4991
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: CREB-binding protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,3462
Polymers13,8481
Non-polymers4991
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
B: CREB-binding protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,3462
Polymers13,8481
Non-polymers4991
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)45.860, 107.010, 55.830
Angle α, β, γ (deg.)90.00, 113.98, 90.00
Int Tables number4
Space group name H-MP1211

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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, residues 1082-1197
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)
References: UniProt: Q92793, histone acetyltransferase, Transferases; Acyltransferases; Transferring groups other than aminoacyl groups
#2: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#3: Chemical
ChemComp-YVK / (6S)-6-{(5M)-5-(3,5-dimethyl-1,2-oxazol-4-yl)-1-[(1s,4R)-4-methoxycyclohexyl]-1H-benzimidazol-2-yl}-1-phenylpiperidin-2-one


Mass: 498.616 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C30H34N4O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 190 / 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: 2.26 Å3/Da / Density % sol: 45.57 %
Crystal growTemperature: 292 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 0.2 M Magnesium chloride hexahydrate; 0.1 M TRIS hydrochloride pH 8.5; 30% w/v Polyethylene glycol 4,000

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Data collection

DiffractionMean temperature: 93 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-D / Wavelength: 1.0332 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Dec 5, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0332 Å / Relative weight: 1
ReflectionResolution: 1.85→46.05 Å / Num. obs: 41493 / % possible obs: 98.7 % / Redundancy: 6.5 % / Biso Wilson estimate: 36.1 Å2 / CC1/2: 0.998 / Rrim(I) all: 0.082 / Net I/σ(I): 16
Reflection shellResolution: 1.85→1.9 Å / Redundancy: 5.2 % / Mean I/σ(I) obs: 4.6 / Num. unique obs: 2829 / CC1/2: 0.844 / Rrim(I) all: 0.666 / % possible all: 91.9

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Processing

Software
NameVersionClassification
PHENIX1.20.1-4487refinement
XDSJan 10, 2022data reduction
XSCALEJan 10, 2022data scaling
PHENIX1.20.1-4487phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.85→46.05 Å / SU ML: 0.2 / Cross valid method: THROUGHOUT / σ(F): 1.4 / Phase error: 24.58 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2252 2075 5 %
Rwork0.1905 --
obs0.1923 41489 98.96 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.85→46.05 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3875 0 152 190 4217
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.008
X-RAY DIFFRACTIONf_angle_d1.159
X-RAY DIFFRACTIONf_dihedral_angle_d9.003538
X-RAY DIFFRACTIONf_chiral_restr0.063580
X-RAY DIFFRACTIONf_plane_restr0.008722
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.85-1.890.33471250.25042374X-RAY DIFFRACTION91
1.89-1.940.28041380.2472615X-RAY DIFFRACTION98
1.94-1.990.28911380.22832631X-RAY DIFFRACTION99
1.99-2.050.24141380.21062632X-RAY DIFFRACTION100
2.05-2.120.24631390.2132626X-RAY DIFFRACTION99
2.12-2.190.24621390.21112648X-RAY DIFFRACTION100
2.19-2.280.25871390.20242649X-RAY DIFFRACTION99
2.28-2.380.24961390.2082625X-RAY DIFFRACTION100
2.39-2.510.21291380.20572630X-RAY DIFFRACTION100
2.51-2.670.26741410.20972685X-RAY DIFFRACTION100
2.67-2.870.27811390.2192640X-RAY DIFFRACTION100
2.87-3.160.23551400.21012644X-RAY DIFFRACTION100
3.16-3.620.23521390.19052652X-RAY DIFFRACTION100
3.62-4.560.18561410.14882673X-RAY DIFFRACTION100
4.56-46.050.17771420.16762690X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: 0.7949 Å / Origin y: 6.2134 Å / Origin z: 17.8269 Å
111213212223313233
T0.1944 Å20.0034 Å2-0.008 Å2-0.194 Å20.0109 Å2--0.1861 Å2
L0.176 °2-0.0069 °2-0.0246 °2-0.3044 °20.0034 °2--0.2343 °2
S0.0205 Å °-0.0221 Å °-0.0281 Å °0.0283 Å °-0.0057 Å °-0.0044 Å °-0.0259 Å °-0.014 Å °-0.0181 Å °
Refinement TLS groupSelection details: all

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