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- PDB-9j6o: Crystal Structure of bromodomain of human CBP in complex with the... -

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Basic information

Entry
Database: PDB / ID: 9j6o
TitleCrystal Structure of bromodomain of human CBP in complex with the inhibitor CZL-046
ComponentsCREB-binding protein
KeywordsPROTEIN BINDING / bromodomain / CBP / inhibitor
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 / N-terminal peptidyl-lysine acetylation / histone H3K18 acetyltransferase activity / LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production / NFE2L2 regulates pentose phosphate pathway genes / histone H3K27 acetyltransferase activity / 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 / N-terminal peptidyl-lysine acetylation / histone H3K18 acetyltransferase activity / LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production / NFE2L2 regulates pentose phosphate pathway genes / histone H3K27 acetyltransferase activity / 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 / positive regulation of double-strand break repair via homologous recombination / cellular response to nutrient levels / histone acetyltransferase activity / 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) / Evasion by RSV of host interferon responses / NOTCH1 Intracellular Domain Regulates Transcription / chromatin DNA binding / Heme signaling / Formation of the beta-catenin:TCF transactivating complex / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / Transcriptional activation of mitochondrial biogenesis / PPARA activates gene expression / protein destabilization / Cytoprotection by HMOX1 / Transcriptional regulation of white adipocyte differentiation / tau protein binding / Pre-NOTCH Transcription and Translation / positive regulation of protein localization to nucleus / Activation of anterior HOX genes in hindbrain development during early embryogenesis / transcription coactivator binding / : / 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 / damaged DNA binding / Estrogen-dependent gene expression / 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 / 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 / : / 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: 2.67 Å
AuthorsZhang, Y. / Zhang, C. / Chen, Z. / Yang, H. / Huang, X. / Li, Y. / Xu, Y.
Funding support China, 1items
OrganizationGrant numberCountry
Ministry of Science and Technology (MoST, China)2022YFE0210600 China
CitationJournal: J.Med.Chem. / Year: 2024
Title: Discovery of CZL-046 with an ( S )-3-Fluoropyrrolidin-2-one Scaffold as a p300 Bromodomain Inhibitor for the Treatment of Multiple Myeloma.
Authors: Chen, Z. / Yang, H. / Zhang, Y. / Lyu, X. / Shi, Q. / Zhang, C. / Wang, X. / Wang, Z. / Zhang, Y. / Deng, Y. / Wang, Y. / Huang, Y. / Xu, Y. / Huang, X. / Li, Y.
History
DepositionAug 16, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 16, 2024Provider: repository / Type: Initial release
Revision 1.1Nov 6, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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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)16,4653
Polymers15,8911
Non-polymers5742
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area70 Å2
ΔGint-3 kcal/mol
Surface area7610 Å2
MethodPISA
Unit cell
Length a, b, c (Å)38.379, 60.637, 61.177
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP22121

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Components

#1: Protein CREB-binding protein


Mass: 15891.296 Da / Num. of mol.: 1 / Fragment: UNP RESIDUES 1081-1197
Source method: isolated from a genetically manipulated source
Details: sequence from 1065-1080 are tags. MKKGHHHHHHLVPRGS / Source: (gene. exp.) Homo sapiens (human) / Gene: CREBBP, CBP / Production host: Escherichia coli BL21 (bacteria) / References: UniProt: Q92793, histone acetyltransferase
#2: Chemical ChemComp-A1L3S / (3~{S},5~{S})-1-[3,4-bis(fluoranyl)phenyl]-5-[5-(3,5-dimethyl-1,2-oxazol-4-yl)-1-(4-methoxycyclohexyl)benzimidazol-2-yl]-3-fluoranyl-pyrrolidin-2-one


Mass: 538.561 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H29F3N4O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
Has ligand of interestY
Has protein modificationN

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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: 2.24 Å3/Da / Density % sol: 45.08 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 0.2 M Potassium sulfate, 20% w/v Polyethylene glycol 3,350

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Data collection

DiffractionMean temperature: 80 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL02U1 / Wavelength: 0.97918 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Jun 21, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 2.67→61.18 Å / Num. obs: 4375 / % possible obs: 99.6 % / Redundancy: 5.8 % / CC1/2: 0.992 / Rmerge(I) obs: 0.162 / Rpim(I) all: 0.073 / Rrim(I) all: 0.178 / Χ2: 0.97 / Net I/σ(I): 9.3 / Num. measured all: 25281
Reflection shellResolution: 2.67→2.8 Å / % possible obs: 99.8 % / Redundancy: 5.1 % / Rmerge(I) obs: 0.654 / Num. measured all: 2861 / Num. unique obs: 564 / CC1/2: 0.82 / Rpim(I) all: 0.323 / Rrim(I) all: 0.732 / Χ2: 0.78 / Net I/σ(I) obs: 2.7

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Processing

Software
NameVersionClassification
REFMAC5.8.0258refinement
Aimlessdata scaling
XDSdata reduction
MERLOTphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7XH6

7xh6


Resolution: 2.67→43.07 Å / Cor.coef. Fo:Fc: 0.914 / Cor.coef. Fo:Fc free: 0.882 / SU B: 16.69 / SU ML: 0.335 / Cross valid method: THROUGHOUT / ESU R Free: 0.399 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.28962 264 6.1 %RANDOM
Rwork0.23438 ---
obs0.23803 4082 99.36 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 39.397 Å2
Baniso -1Baniso -2Baniso -3
1--1.64 Å2-0 Å20 Å2
2--2.98 Å2-0 Å2
3----1.34 Å2
Refinement stepCycle: 1 / Resolution: 2.67→43.07 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms998 0 40 0 1038
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0131070
X-RAY DIFFRACTIONr_bond_other_d0.0020.018964
X-RAY DIFFRACTIONr_angle_refined_deg1.3061.721458
X-RAY DIFFRACTIONr_angle_other_deg1.1061.6312248
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4545117
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.84523.05159
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.11115180
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.517156
X-RAY DIFFRACTIONr_chiral_restr0.0510.2130
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.021152
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02219
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.3184.127474
X-RAY DIFFRACTIONr_mcbond_other1.3194.127473
X-RAY DIFFRACTIONr_mcangle_it2.2176.186589
X-RAY DIFFRACTIONr_mcangle_other2.2156.186590
X-RAY DIFFRACTIONr_scbond_it1.4364.336596
X-RAY DIFFRACTIONr_scbond_other1.4344.336597
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other2.4976.432870
X-RAY DIFFRACTIONr_long_range_B_refined3.99545.4811180
X-RAY DIFFRACTIONr_long_range_B_other3.99445.471181
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.67→2.737 Å
RfactorNum. reflection% reflection
Rfree0.428 21 -
Rwork0.243 284 -
obs--99.67 %

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