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- PDB-5kj2: The novel p300/CBP inhibitor A-485 uncovers a unique mechanism of... -

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Basic information

Entry
Database: PDB / ID: 5kj2
TitleThe novel p300/CBP inhibitor A-485 uncovers a unique mechanism of action to target AR in castrate resistant prostate cancer
ComponentsHistone acetyltransferase p300
Keywordstransferase/transferase INHIBITOR / Histone Acetyltransferase / transferase-transferase INHIBITOR complex
Function / homology
Function and homology information


behavioral defense response / peptidyl-lysine propionylation / histone lactyltransferase (CoA-dependent) activity / peptidyl-lysine crotonylation / peptidyl-lysine butyrylation / histone butyryltransferase activity / histone H3K122 acetyltransferase activity / swimming / peptide butyryltransferase activity / histone H2B acetyltransferase activity ...behavioral defense response / peptidyl-lysine propionylation / histone lactyltransferase (CoA-dependent) activity / peptidyl-lysine crotonylation / peptidyl-lysine butyrylation / histone butyryltransferase activity / histone H3K122 acetyltransferase activity / swimming / peptide butyryltransferase activity / histone H2B acetyltransferase activity / thigmotaxis / peptide 2-hydroxyisobutyryltransferase activity / histone crotonyltransferase activity / protein propionyltransferase activity / NOTCH2 intracellular domain regulates transcription / peptidyl-lysine acetylation / lysine N-acetyltransferase activity, acting on acetyl phosphate as donor / cellular response to L-leucine / histone H4 acetyltransferase activity / internal peptidyl-lysine acetylation / histone H3 acetyltransferase activity / 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 / acetylation-dependent protein binding / NGF-stimulated transcription / STAT3 nuclear events downstream of ALK signaling / Polo-like kinase mediated events / histone H3K18 acetyltransferase activity / LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production / N-terminal peptidyl-lysine acetylation / histone H3K27 acetyltransferase activity / NFE2L2 regulates pentose phosphate pathway genes / NFE2L2 regulating MDR associated enzymes / regulation of androgen receptor signaling pathway / positive regulation by host of viral transcription / regulation of mitochondrion organization / Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells / RUNX3 regulates NOTCH signaling / face morphogenesis / Regulation of FOXO transcriptional activity by acetylation / NOTCH4 Intracellular Domain Regulates Transcription / Regulation of gene expression by Hypoxia-inducible Factor / regulation of glycolytic process / Nuclear events mediated by NFE2L2 / Regulation of NFE2L2 gene expression / NOTCH3 Intracellular Domain Regulates Transcription / platelet formation / NFE2L2 regulating anti-oxidant/detoxification enzymes / TRAF6 mediated IRF7 activation / megakaryocyte development / NFE2L2 regulating tumorigenic genes / peptide-lysine-N-acetyltransferase activity / FOXO-mediated transcription of cell death genes / macrophage derived foam cell differentiation / nuclear androgen receptor binding / regulation of tubulin deacetylation / STAT family protein binding / internal protein amino acid acetylation / acyltransferase activity / protein acetylation / positive regulation of transforming growth factor beta receptor signaling pathway / fat cell differentiation / Formation of paraxial mesoderm / RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known / PI5P Regulates TP53 Acetylation / Zygotic genome activation (ZGA) / stimulatory C-type lectin receptor signaling pathway / cellular response to nutrient levels / RUNX3 regulates p14-ARF / acetyltransferase activity / NF-kappaB binding / histone acetyltransferase complex / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / Attenuation phase / canonical NF-kappaB signal transduction / negative regulation of protein-containing complex assembly / negative regulation of gluconeogenesis / somitogenesis / positive regulation of T-helper 17 cell lineage commitment / pre-mRNA intronic binding / regulation of cellular response to heat / SARS-CoV-1 targets host intracellular signalling and regulatory pathways / histone acetyltransferase activity / skeletal muscle tissue development / histone acetyltransferase / transcription initiation-coupled chromatin remodeling / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / Transferases; Acyltransferases; Transferring groups other than aminoacyl groups / Regulation of TP53 Activity through Acetylation / positive regulation of TORC1 signaling / RORA activates gene expression / CD209 (DC-SIGN) signaling / negative regulation of autophagy / B cell differentiation / TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest / SUMOylation of transcription cofactors / regulation of signal transduction by p53 class mediator / regulation of autophagy
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, conserved site / Bromodomain signature. / Bromodomain / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily / Zinc finger, RING/FYVE/PHD-type
Similarity search - Domain/homology
Chem-6TF / Histone acetyltransferase p300
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.95 Å
AuthorsJakob, C.G. / Qiu, W. / Edalji, R.P. / Sun, C.
CitationJournal: Nature / Year: 2017
Title: Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours.
Authors: Lasko, L.M. / Jakob, C.G. / Edalji, R.P. / Qiu, W. / Montgomery, D. / Digiammarino, E.L. / Hansen, T.M. / Risi, R.M. / Frey, R. / Manaves, V. / Shaw, B. / Algire, M. / Hessler, P. / Lam, L.T. ...Authors: Lasko, L.M. / Jakob, C.G. / Edalji, R.P. / Qiu, W. / Montgomery, D. / Digiammarino, E.L. / Hansen, T.M. / Risi, R.M. / Frey, R. / Manaves, V. / Shaw, B. / Algire, M. / Hessler, P. / Lam, L.T. / Uziel, T. / Faivre, E. / Ferguson, D. / Buchanan, F.G. / Martin, R.L. / Torrent, M. / Chiang, G.G. / Karukurichi, K. / Langston, J.W. / Weinert, B.T. / Choudhary, C. / de Vries, P. / Van Drie, J.H. / McElligott, D. / Kesicki, E. / Marmorstein, R. / Sun, C. / Cole, P.A. / Rosenberg, S.H. / Michaelides, M.R. / Lai, A. / Bromberg, K.D.
History
DepositionJun 17, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 27, 2017Provider: repository / Type: Initial release
Revision 2.0Nov 1, 2017Group: Non-polymer description / Structure summary / Category: entity
Item: _chem_comp.formula / _chem_comp.name ..._chem_comp.formula / _chem_comp.name / _chem_comp.pdbx_synonyms / _entity.formula_weight / _entity.pdbx_description
Revision 2.1Apr 10, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _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
Revision 2.2Sep 27, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Histone acetyltransferase p300
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,8203
Polymers40,2611
Non-polymers5592
Water4,666259
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area150 Å2
ΔGint-9 kcal/mol
Surface area15370 Å2
MethodPISA
Unit cell
Length a, b, c (Å)45.192, 102.944, 168.438
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221

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Components

#1: Protein Histone acetyltransferase p300 / p300 HAT / E1A-associated protein p300


Mass: 40261.000 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EP300, P300 / Production host: Escherichia coli (E. coli) / References: UniProt: Q09472, histone acetyltransferase
#2: Chemical ChemComp-6TF / N-[(4-fluorophenyl)methyl]-2-{(1R)-5-[(methylcarbamoyl)amino]-2',4'-dioxo-2,3-dihydro-3'H-spiro[indene-1,5'-[1,3]oxazolidin]-3'-yl}-N-[(2S)-1,1,1-trifluoropropan-2-yl]acetamide / N-(4-fluorobenzyl)-2-((R)-5-(3-methylureido)-2',4'-dioxo-2,3-dihydrospiro[indene-1,5'-ozazolidine]-3'-yl)-N-((S)-1,1,1-trifluoropropan-2-yl)acetamide


Mass: 536.475 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H24F4N4O5
#3: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 259 / Source method: isolated from a natural source / Formula: H2O

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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: 2.61 Å3/Da / Density % sol: 52.92 %
Crystal growTemperature: 290 K / Method: vapor diffusion
Details: 25% (w/v) PEG3350, 0.2M Sodium Chloride, 0.1M BIS-TRIS buffer pH5.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Oct 8, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.95→168.44 Å / Num. obs: 29345 / % possible obs: 100 % / Redundancy: 6.6 % / Biso Wilson estimate: 34.95 Å2 / Net I/σ(I): 20.3
Reflection shellResolution: 1.947→1.953 Å / Redundancy: 6.9 % / Rmerge(I) obs: 0.87 / Mean I/σ(I) obs: 2.2 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3BIY

3biy


Resolution: 1.95→24.39 Å / Cor.coef. Fo:Fc: 0.936 / Cor.coef. Fo:Fc free: 0.917 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.177 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.188 / SU Rfree Blow DPI: 0.164 / SU Rfree Cruickshank DPI: 0.159
RfactorNum. reflection% reflectionSelection details
Rfree0.26 1414 4.85 %RANDOM
Rwork0.225 ---
obs0.227 29145 100 %-
Displacement parametersBiso mean: 39.78 Å2
Baniso -1Baniso -2Baniso -3
1-3.4996 Å20 Å20 Å2
2---0.3852 Å20 Å2
3----3.1144 Å2
Refine analyzeLuzzati coordinate error obs: 0.31 Å
Refinement stepCycle: LAST / Resolution: 1.95→24.39 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2586 0 39 259 2884
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012699HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.113665HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d915SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes62HARMONIC2
X-RAY DIFFRACTIONt_gen_planes399HARMONIC5
X-RAY DIFFRACTIONt_it2699HARMONIC20
X-RAY DIFFRACTIONt_nbd3SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion3.3
X-RAY DIFFRACTIONt_other_torsion18
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion338SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact3236SEMIHARMONIC4
LS refinement shellResolution: 1.95→2.02 Å / Rfactor Rfree error: 0 / Total num. of bins used: 15
RfactorNum. reflection% reflection
Rfree0.314 132 4.7 %
Rwork0.26 2677 -
all0.263 2809 -
obs--99.93 %

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