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- PDB-5xxh: Crystal Structure Analysis of the CBP -

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Basic information

Entry
Database: PDB / ID: 5xxh
TitleCrystal Structure Analysis of the CBP
ComponentsCREB-binding protein
KeywordsTRANSFERASE / CBP / Bromodomain
Function / homology
Function and homology information


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 H3K27 acetyltransferase activity / regulation of smoothened signaling pathway / histone H3K18 acetyltransferase activity / N-terminal peptidyl-lysine acetylation / LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production / MRF binding ...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 H3K27 acetyltransferase activity / regulation of smoothened signaling pathway / histone H3K18 acetyltransferase activity / N-terminal peptidyl-lysine acetylation / LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production / MRF binding / NFE2L2 regulates pentose phosphate pathway genes / NFE2L2 regulating MDR associated enzymes / 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 / negative regulation of transcription by RNA polymerase I / NOTCH4 Intracellular Domain Regulates Transcription / Regulation of FOXO transcriptional activity by acetylation / Regulation of gene expression by Hypoxia-inducible Factor / Nuclear events mediated by NFE2L2 / Regulation of NFE2L2 gene expression / NOTCH3 Intracellular Domain Regulates Transcription / TRAF6 mediated IRF7 activation / peptide-lysine-N-acetyltransferase activity / NFE2L2 regulating anti-oxidant/detoxification enzymes / FOXO-mediated transcription of cell death genes / NFE2L2 regulating tumorigenic genes / embryonic digit morphogenesis / homeostatic process / Notch-HLH transcription pathway / protein acetylation / Formation of paraxial mesoderm / positive regulation of transforming growth factor beta receptor signaling pathway / non-canonical NF-kappaB signal transduction / Zygotic genome activation (ZGA) / acetyltransferase activity / stimulatory C-type lectin receptor signaling pathway / cellular response to nutrient levels / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / 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 / protein destabilization / Heme signaling / Transcriptional activation of mitochondrial biogenesis / transcription coactivator binding / PPARA activates gene expression / Cytoprotection by HMOX1 / chromatin DNA binding / NOTCH1 Intracellular Domain Regulates Transcription / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / Pre-NOTCH Transcription and Translation / Activation of anterior HOX genes in hindbrain development during early embryogenesis / Transcriptional regulation of white adipocyte differentiation / 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 / transcription regulator complex / RNA polymerase II-specific DNA-binding transcription factor binding / damaged DNA binding / transcription coactivator activity / response to hypoxia / nuclear body / chromatin binding / chromatin / regulation of DNA-templated transcription / 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
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-E0D / CREB-binding protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.62 Å
AuthorsXiang, Q. / Zhang, Y. / Wang, C. / Song, M.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Eur J Med Chem / Year: 2018
Title: Discovery and optimization of 1-(1H-indol-1-yl)ethanone derivatives as CBP/EP300 bromodomain inhibitors for the treatment of castration-resistant prostate cancer.
Authors: Xiang, Q. / Wang, C. / Zhang, Y. / Xue, X. / Song, M. / Zhang, C. / Li, C. / Wu, C. / Li, K. / Hui, X. / Zhou, Y. / Smaill, J.B. / Patterson, A.V. / Wu, D. / Ding, K. / Xu, Y.
History
DepositionJul 4, 2017Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 13, 2018Provider: repository / Type: Initial release
Revision 2.0Oct 18, 2023Group: Atomic model / Author supporting evidence ...Atomic model / Author supporting evidence / Data collection / Database references / Derived calculations / Other / Refinement description / Source and taxonomy / Structure summary
Category: atom_site / atom_sites ...atom_site / atom_sites / chem_comp_atom / chem_comp_bond / database_2 / diffrn / entity_src_gen / pdbx_audit_support / pdbx_contact_author / pdbx_entity_instance_feature / pdbx_entry_details / pdbx_nonpoly_scheme / pdbx_struct_assembly_prop / pdbx_struct_conn_angle / refine / refine_hist / refine_ls_restr / refine_ls_shell / reflns_shell / struct_conn / struct_site / struct_site_gen
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_sites.fract_transf_matrix[2][1] / _atom_sites.fract_transf_matrix[3][2] / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _diffrn.pdbx_serial_crystal_experiment / _entity_src_gen.gene_src_common_name / _entity_src_gen.pdbx_host_org_scientific_name / _entity_src_gen.pdbx_host_org_strain / _pdbx_contact_author.id / _pdbx_contact_author.identifier_ORCID / _pdbx_nonpoly_scheme.auth_seq_num / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_symmetry / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_symmetry / _pdbx_struct_conn_angle.value / _refine.B_iso_mean / _refine.aniso_B[2][3] / _refine.details / _refine.ls_R_factor_R_free / _refine.ls_R_factor_R_work / _refine.ls_R_factor_obs / _refine.ls_percent_reflns_obs / _refine_hist.pdbx_B_iso_mean_solvent / _refine_ls_shell.d_res_high / _refine_ls_shell.d_res_low / _struct_conn.pdbx_dist_value / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_symmetry
Description: Occupancy of atoms on special symmetry positions
Provider: author / Type: Coordinate replacement
Revision 2.1Nov 22, 2023Group: Refinement description / Category: pdbx_initial_refinement_model

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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)16,3064
Polymers15,8911
Non-polymers4153
Water2,198122
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)44.320, 44.320, 121.292
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number154
Space group name H-MP3221

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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
Source: (gene. exp.) Homo sapiens (human) / Gene: CREBBP, CBP / Production host: Escherichia coli BL21 (bacteria) / References: UniProt: Q92793, histone acetyltransferase
#2: Chemical ChemComp-E0D / (3S)-1-[2-(3-ethanoylindol-1-yl)ethanoyl]piperidine-3-carboxylic acid


Mass: 328.362 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H20N2O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 122 / 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: 2.16 Å3/Da / Density % sol: 43.16 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8.5 / Details: 30% PEG 3350, 0.2M MgCl2, 0.1M Tris HCl, PH 8.5

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Data collection

DiffractionMean temperature: 80 K / Ambient temp details: liquid nitrogen / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL18U1 / Wavelength: 0.97791 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Mar 25, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97791 Å / Relative weight: 1
ReflectionResolution: 1.62→60.65 Å / Num. obs: 18496 / % possible obs: 100 % / Redundancy: 17.4 % / CC1/2: 0.998 / Rmerge(I) obs: 0.085 / Rpim(I) all: 0.021 / Rrim(I) all: 0.088 / Net I/σ(I): 22.2 / Num. measured all: 322175 / Scaling rejects: 291
Reflection shellResolution: 1.62→1.64 Å / Redundancy: 18.6 % / Rmerge(I) obs: 0.335 / Num. measured all: 16584 / Num. unique obs: 894 / CC1/2: 0.985 / Rpim(I) all: 0.08 / Rrim(I) all: 0.344 / Net I/σ(I) obs: 9.6 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.8.0135refinement
Aimless0.5.23data scaling
PDB_EXTRACT3.22data extraction
iMOSFLMdata reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4NYX

4nyx


Resolution: 1.62→40.43 Å / Cor.coef. Fo:Fc: 0.952 / Cor.coef. Fo:Fc free: 0.934 / SU B: 1.43 / SU ML: 0.051 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.092 / ESU R Free: 0.087 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.208 859 4.7 %RANDOM
Rwork0.191 ---
obs0.192 17589 100 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 46.9 Å2 / Biso mean: 17.71 Å2 / Biso min: 9.37 Å2
Baniso -1Baniso -2Baniso -3
1-0.07 Å20.04 Å20 Å2
2--0.07 Å20 Å2
3----0.23 Å2
Refinement stepCycle: final / Resolution: 1.62→40.43 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms973 0 29 122 1124
Biso mean--16.64 24.51 -
Num. residues----117
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.021038
X-RAY DIFFRACTIONr_bond_other_d0.0040.02976
X-RAY DIFFRACTIONr_angle_refined_deg1.332.0031408
X-RAY DIFFRACTIONr_angle_other_deg0.9573.0062257
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.1565118
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.92924.4949
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.12815181
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.264156
X-RAY DIFFRACTIONr_chiral_restr0.070.2145
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0211141
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02231
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_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.62→1.66 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.195 57 -
Rwork0.213 1271 -
all-1328 -
obs--100 %

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