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- PDB-2d82: Target Structure-Based Discovery of Small Molecules that Block Hu... -

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Basic information

Entry
Database: PDB / ID: 2d82
TitleTarget Structure-Based Discovery of Small Molecules that Block Human p53 and CREB Binding Protein (CBP) Association
ComponentsCREB-binding protein
KeywordsTRANSFERASE / Bromodomain / CREB / CBP / p53 / Chemical Ligand / 9-Acetyl-2 / 3 / 4 / 9-tetrahydro-carbazol-1-one
Function / homology
Function and homology information


peptide lactyltransferase (CoA-dependent) activity / NFE2L2 regulating ER-stress associated genes / protein N-acetyltransferase activity / Activation of the TFAP2 (AP-2) family of transcription factors / NFE2L2 regulating inflammation associated genes / histone lactyltransferase (CoA-dependent) activity / N-terminal peptidyl-lysine acetylation / regulation of smoothened signaling pathway / LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production / NFE2L2 regulates pentose phosphate pathway genes ...peptide lactyltransferase (CoA-dependent) activity / NFE2L2 regulating ER-stress associated genes / protein N-acetyltransferase activity / Activation of the TFAP2 (AP-2) family of transcription factors / NFE2L2 regulating inflammation associated genes / histone lactyltransferase (CoA-dependent) activity / N-terminal peptidyl-lysine acetylation / regulation of smoothened signaling pathway / 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 / Nuclear events mediated by NFE2L2 / NOTCH4 Intracellular Domain Regulates Transcription / Regulation of NFE2L2 gene expression / Regulation of gene expression by Hypoxia-inducible Factor / negative regulation of transcription by RNA polymerase I / NOTCH3 Intracellular Domain Regulates Transcription / TRAF6 mediated IRF7 activation / NFE2L2 regulating tumorigenic genes / NFE2L2 regulating anti-oxidant/detoxification enzymes / protein-lysine-acetyltransferase activity / embryonic digit morphogenesis / protein acetylation / homeostatic process / Notch-HLH transcription pathway / histone acetyltransferase activity / positive regulation of transforming growth factor beta receptor signaling pathway / Formation of paraxial mesoderm / 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 / positive regulation of double-strand break repair via homologous recombination / cellular response to nutrient levels / Transcriptional and post-translational regulation of MITF-M expression and activity / Attenuation phase / histone H4K16 acetyltransferase activity / histone H3K56 acetyltransferase activity / histone H3K23 acetyltransferase activity / histone H2AK5 acetyltransferase activity / histone H2AK9 acetyltransferase activity / histone H2BK5 acetyltransferase activity / histone H2BK12 acetyltransferase activity / histone H3K4 acetyltransferase activity / histone H3K27 acetyltransferase activity / histone H3K36 acetyltransferase activity / histone H3K122 acetyltransferase activity / regulation of cellular response to heat / histone H3K18 acetyltransferase activity / histone H3K9 acetyltransferase activity / histone H3K14 acetyltransferase activity / histone H4K5 acetyltransferase activity / histone H4K8 acetyltransferase activity / histone H4K12 acetyltransferase activity / histone acetyltransferase / : / Regulation of lipid metabolism by PPARalpha / NPAS4 regulates expression of target genes / Transferases; Acyltransferases; Transferring groups other than aminoacyl groups / CD209 (DC-SIGN) signaling / BMAL1:CLOCK,NPAS2 activates circadian expression / SUMOylation of transcription cofactors / Activation of gene expression by SREBF (SREBP) / transcription coactivator binding / Heme signaling / Formation of the beta-catenin:TCF transactivating complex / Transcriptional activation of mitochondrial biogenesis / PPARA activates gene expression / Cytoprotection by HMOX1 / protein destabilization / Evasion by RSV of host interferon responses / chromatin DNA binding / Transcriptional regulation of white adipocyte differentiation / NOTCH1 Intracellular Domain Regulates Transcription / Pre-NOTCH Transcription and Translation / positive regulation of protein localization to nucleus / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / Activation of anterior HOX genes in hindbrain development during early embryogenesis / transcription corepressor activity / cellular response to UV / p53 binding / : / rhythmic process / HATs acetylate histones / TRAF3-dependent IRF activation pathway / MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis / protein-containing complex assembly / DNA-binding transcription factor binding / transcription regulator complex / RNA polymerase II-specific DNA-binding transcription factor binding / Estrogen-dependent gene expression
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
9-ACETYL-2,3,4,9-TETRAHYDRO-1H-CARBAZOL-1-ONE / CREB-binding protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodSOLUTION NMR / Distance Geometry, Simulated Annealing
AuthorsSachchidanand / Resnick-Silverman, L. / Yan, S. / Mujtaba, S. / Liu, W.J. / Zeng, L. / Manfredi, J.J. / Zhou, M.M.
CitationJournal: Chem.Biol. / Year: 2006
Title: Target structure-based discovery of small molecules that block human p53 and CREB binding protein association
Authors: Sachchidanand / Resnick-Silverman, L. / Yan, S. / Mutjaba, S. / Liu, W.J. / Zeng, L. / Manfredi, J.J. / Zhou, M.M.
History
DepositionDec 1, 2005Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 4, 2006Provider: repository / Type: Initial release
Revision 1.1Apr 30, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Mar 9, 2022Group: Data collection / Database references / Derived calculations
Category: database_2 / pdbx_nmr_software ...database_2 / pdbx_nmr_software / pdbx_struct_assembly / pdbx_struct_oper_list / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_nmr_software.name / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.4May 29, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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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)14,6462
Polymers14,4191
Non-polymers2271
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
NMR ensembles
DataCriteria
Number of conformers (submitted / calculated)1 / 200structures with the least restraint violations
RepresentativeModel #1fewest violations

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Components

#1: Protein CREB-binding protein / CBP


Mass: 14418.547 Da / Num. of mol.: 1 / Fragment: Bromodomain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Plasmid: PET15B / Species (production host): Escherichia coli / Production host: Escherichia coli BL21 (bacteria) / Strain (production host): BL21 / References: UniProt: Q92793, histone acetyltransferase
#2: Chemical ChemComp-TTR / 9-ACETYL-2,3,4,9-TETRAHYDRO-1H-CARBAZOL-1-ONE


Mass: 227.259 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H13NO2

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Experimental details

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Experiment

ExperimentMethod: SOLUTION NMR
NMR experiment
Conditions-IDExperiment-IDSolution-IDType
1113D 13C-SEPERATED NOESY, 3D 13C-SEPERATED TOCSY
1213D 13C-EDITED 13C/15N-Filtered NOESY
1323D HN(CA)CB, 3D HN(CO)CACB, 3D C(CO)NH
NMR detailsText: The structure was determined using triple-resonance NMR spectroscopy.

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Sample preparation

Details
Solution-IDContentsSolvent system
10.5MM CBP BROMODOMAIN U-15N, 13C; 3.0MM CRB Ligand; 100MM PHOSPHATE BUFFER; PH 6.5100% D2O
20.5MM CBP BROMODOMAIN U-15N, 13C, 75% 2H; 3.0MM CRB Ligand; 100MM PHOSPHATE BUFFER; PH 6.590% H2O/10% D2O
Sample conditionspH: 6.5 / Pressure: AMBIENT / Temperature: 298 K

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NMR measurement

NMR spectrometer
TypeManufacturerModelField strength (MHz)Spectrometer-ID
Bruker DRXBrukerDRX8001
Bruker DRXBrukerDRX6002
Bruker DRXBrukerDRX5003

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Processing

NMR software
NameVersionDeveloperClassification
NMRPipe2.3F.Delaglio, S.Grzesiek, G.Vuister, G.Zhu, J.Pfeifer, A.Baxprocessing
NMRView5.0.4Bruce A.Johnsondata analysis
X-PLOR3.851Brungerstructure solution
ARIA2M.Nilges, S.O'Donoghuerefinement
RefinementMethod: Distance Geometry, Simulated Annealing / Software ordinal: 1
NMR representativeSelection criteria: fewest violations
NMR ensembleConformer selection criteria: structures with the least restraint violations
Conformers calculated total number: 200 / Conformers submitted total number: 1

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