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- PDB-5nu5: Crystal structure of the human bromodomain of EP300 bound to the ... -

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Basic information

Entry
Database: PDB / ID: 5nu5
TitleCrystal structure of the human bromodomain of EP300 bound to the inhibitor XDM-CBP
ComponentsHistone acetyltransferase p300
KeywordsTRANSFERASE / bromodomain / protein-inhibitor complex / epigenetics / EP300
Function / homology
Function and homology information


behavioral defense response / negative regulation of protein oligomerization / peptidyl-lysine propionylation / histone lactyltransferase (CoA-dependent) activity / peptidyl-lysine crotonylation / peptidyl-lysine butyrylation / histone butyryltransferase activity / swimming / peptide butyryltransferase activity / regulation of tubulin deacetylation ...behavioral defense response / negative regulation of protein oligomerization / peptidyl-lysine propionylation / histone lactyltransferase (CoA-dependent) activity / peptidyl-lysine crotonylation / peptidyl-lysine butyrylation / histone butyryltransferase activity / swimming / peptide butyryltransferase activity / regulation of tubulin deacetylation / histone H2B acetyltransferase activity / internal protein amino acid acetylation / peptide 2-hydroxyisobutyryltransferase activity / histone crotonyltransferase activity / protein propionyltransferase activity / NOTCH2 intracellular domain regulates transcription / thigmotaxis / L-lysine N-acetyltransferase activity, acting on acetyl phosphate as donor / positive regulation of TORC2 signaling / internal peptidyl-lysine acetylation / histone H4 acetyltransferase activity / cellular response to L-leucine / histone H3 acetyltransferase activity / NFE2L2 regulating ER-stress associated genes / acetylation-dependent protein binding / Activation of the TFAP2 (AP-2) family of transcription factors / NFE2L2 regulating inflammation associated genes / NGF-stimulated transcription / N-terminal peptidyl-lysine acetylation / LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production / NFE2L2 regulates pentose phosphate pathway genes / STAT3 nuclear events downstream of ALK signaling / Polo-like kinase mediated events / NFE2L2 regulating MDR associated enzymes / host-mediated activation of viral transcription / TGFBR3 expression / regulation of androgen receptor signaling pathway / regulation of mitochondrion organization / 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 / face morphogenesis / platelet formation / NOTCH3 Intracellular Domain Regulates Transcription / regulation of glycolytic process / TRAF6 mediated IRF7 activation / NFE2L2 regulating tumorigenic genes / NFE2L2 regulating anti-oxidant/detoxification enzymes / megakaryocyte development / protein-lysine-acetyltransferase activity / nuclear androgen receptor binding / acyltransferase activity / STAT family protein binding / protein acetylation / histone H3K122 acetyltransferase activity / Formation of paraxial mesoderm / positive regulation of transforming growth factor beta receptor signaling pathway / acetyltransferase activity / histone H3K18 acetyltransferase activity / FOXO-mediated transcription of cell death genes / PI5P Regulates TP53 Acetylation / histone H3K27 acetyltransferase activity / stimulatory C-type lectin receptor signaling pathway / fat cell differentiation / RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known / Zygotic genome activation (ZGA) / histone acetyltransferase activity / histone acetyltransferase complex / RUNX3 regulates p14-ARF / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / canonical NF-kappaB signal transduction / NF-kappaB binding / negative regulation of gluconeogenesis / pre-mRNA intronic binding / Attenuation phase / somitogenesis / negative regulation of protein-containing complex assembly / positive regulation of T-helper 17 cell lineage commitment / cellular response to nutrient levels / skeletal muscle tissue development / histone acetyltransferase / regulation of cellular response to heat / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / SARS-CoV-1 targets host intracellular signalling and regulatory pathways / positive regulation of DNA-binding transcription factor activity / Regulation of TP53 Activity through Acetylation / : / Transferases; Acyltransferases; Transferring groups other than aminoacyl groups / positive regulation of TORC1 signaling / Transcriptional and post-translational regulation of MITF-M expression and activity / CD209 (DC-SIGN) signaling / negative regulation of autophagy / B cell differentiation / transcription initiation-coupled chromatin remodeling / SUMOylation of transcription cofactors / TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest
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-like / Histone Acetyltransferase; Chain A / Bromodomain, conserved site / Bromodomain signature. / Bromodomain / bromo domain / Bromodomain / Bromodomain (BrD) profile. / Bromodomain-like superfamily / Zinc finger, RING/FYVE/PHD-type / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-99E / Histone acetyltransferase p300
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.6 Å
AuthorsHuegle, M. / Wohlwend, D.
Funding support Germany, 1items
OrganizationGrant numberCountry
German Research FoundationWO 2012/1-1 Germany
CitationJournal: Angew. Chem. Int. Ed. Engl. / Year: 2017
Title: Beyond the BET Family: Targeting CBP/p300 with 4-Acyl Pyrroles.
Authors: Hugle, M. / Lucas, X. / Ostrovskyi, D. / Regenass, P. / Gerhardt, S. / Einsle, O. / Hau, M. / Jung, M. / Breit, B. / Gunther, S. / Wohlwend, D.
History
DepositionApr 28, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 16, 2017Provider: repository / Type: Initial release
Revision 1.1Oct 11, 2017Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 1.2Jan 17, 2024Group: 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
B: Histone acetyltransferase p300
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,6979
Polymers27,6542
Non-polymers1,0437
Water6,215345
1
A: Histone acetyltransferase p300
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,4416
Polymers13,8271
Non-polymers6155
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Histone acetyltransferase p300
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,2553
Polymers13,8271
Non-polymers4282
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)37.920, 82.433, 42.608
Angle α, β, γ (deg.)90.000, 110.770, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 13826.797 Da / Num. of mol.: 2 / Fragment: bromodomain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EP300, P300 / Plasmid: pNIC28-Bsa4 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q09472, histone acetyltransferase
#2: Chemical ChemComp-99E / ~{N}-[[2,8-bis(oxidanyl)naphthalen-1-yl]methyl]-4-ethanoyl-3-ethyl-5-methyl-1~{H}-pyrrole-2-carboxamide


Mass: 366.410 Da / Num. of mol.: 2 / Fragment: XDM4 / Source method: obtained synthetically / Formula: C21H22N2O4
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 345 / 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: 2.25 Å3/Da / Density % sol: 45.37 % / Mosaicity: 0.17 °
Crystal growTemperature: 277 K / Method: evaporation / pH: 6.5 / Details: KSCN, NaBr, PEG 6000, PEG 8000, PEG 10000

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Feb 8, 2016
RadiationMonochromator: Fixed-exit LN2 cooled Double Crystal Monochromator
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.6→41.22 Å / Num. obs: 31598 / % possible obs: 97.9 % / Redundancy: 3.4 % / CC1/2: 0.998 / Rmerge(I) obs: 0.051 / Rpim(I) all: 0.033 / Rrim(I) all: 0.061 / Net I/σ(I): 14.2 / Num. measured all: 108101 / Scaling rejects: 30
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsCC1/2Rpim(I) allRrim(I) all% possible all
1.6-1.633.50.4190.80.2630.49697.9
8.76-41.223.40.0260.9980.0180.03194.6

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation2.58 Å41.22 Å
Translation2.58 Å41.22 Å

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimless0.5.32data scaling
PHASER2.7.16phasing
REFMAC5.8.0135refinement
PDB_EXTRACT3.22data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4NYX

4nyx


Resolution: 1.6→41.22 Å / Cor.coef. Fo:Fc: 0.97 / Cor.coef. Fo:Fc free: 0.953 / SU B: 3.036 / SU ML: 0.057 / SU R Cruickshank DPI: 0.0923 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.092 / ESU R Free: 0.087
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.1854 1483 4.7 %RANDOM
Rwork0.1624 ---
obs0.1634 30091 97.76 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 55.45 Å2 / Biso mean: 20.09 Å2 / Biso min: 10.5 Å2
Baniso -1Baniso -2Baniso -3
1-0.99 Å20 Å20.1 Å2
2---0.84 Å20 Å2
3----0.18 Å2
Refinement stepCycle: final / Resolution: 1.6→41.22 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1943 0 74 362 2379
Biso mean--23.02 31.52 -
Num. residues----232
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.022148
X-RAY DIFFRACTIONr_bond_other_d0.0020.022013
X-RAY DIFFRACTIONr_angle_refined_deg1.3532.0122926
X-RAY DIFFRACTIONr_angle_other_deg0.90434657
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.8835248
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.32924.327104
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.80215375
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.2561514
X-RAY DIFFRACTIONr_chiral_restr0.0670.2295
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0212394
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02490
LS refinement shellResolution: 1.6→1.642 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.225 109 -
Rwork0.242 2231 -
all-2340 -
obs--98.15 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.5968-0.11120.00197.52221.1691.60850.01830.01740.2596-0.239-0.0009-0.1063-0.2196-0.0421-0.01740.0382-0.01150.01780.043-0.02510.062250.994327.835713.8116
29.9761-3.07190.48194.4823-0.89023.99510.04110.194-0.1689-0.28560.0231-0.28680.21570.1782-0.06420.0408-0.0020.02030.016-0.01740.039547.35428.8149.9591
33.97622.71261.08964.33761.72964.6961-0.0296-0.0992-0.0256-0.10550.10250.41170.2587-0.3099-0.07290.0291-0.0282-0.03340.04750.04950.088730.89549.381112.6065
41.472-0.13910.43111.8175-1.08121.6101-0.03990.03780.1586-0.36050.0182-0.04290.0778-0.06810.02170.0152-0.0078-0.00260.0204-0.00460.024542.634924.00439.8905
51.62961.6627-0.0258.6207-0.92591.43760.011-0.21760.15710.33220.028-0.0211-0.10220.0373-0.0390.01770.0071-0.00460.0414-0.03060.022643.553623.185720.2009
63.5365-0.9249-0.70563.19550.39042.4984-0.1009-0.2426-0.19670.10970.14070.05620.2859-0.1016-0.03980.0341-0.0081-0.00310.0290.01890.013640.67844.227920.2636
77.9642-0.33620.19183.78623.65843.5697-0.0182-0.0021-0.2940.20670.0821-0.05490.20410.082-0.06380.05380.01460.0160.05740.00170.083851.480910.301319.4303
83.40623.6254-0.107112.30260.54383.287-0.0495-0.25470.13040.24710.0267-0.3138-0.15790.08830.02280.03570.0007-0.01830.0886-0.03970.062754.406523.570522.3827
95.56130.8729-3.15148.0553-1.81082.3907-0.1039-0.2235-0.4128-0.2718-0.0336-0.24680.3790.09420.13750.2162-0.0399-0.06130.0783-0.02470.116823.22879.159-2.8399
102.0163.8715-0.1747.5024-0.24661.7324-0.42790.2158-0.0018-0.8670.3552-0.0231-0.0318-0.02990.07270.1664-0.03490.01920.09470.01740.014322.052727.536-7.9467
112.73070.66721.57193.7150.1013.1048-0.20780.05920.0873-0.04020.216-0.4706-0.27840.2797-0.00820.0273-0.0229-0.0010.0442-0.03780.075333.958834.79133.8436
123.3582-0.05480.34085.05340.4912.37660.0382-0.0103-0.2579-0.19220.0722-0.24680.1140.114-0.11050.01490.00320.00320.0061-0.00560.033827.027218.58730.7721
132.7281-0.57840.42413.99630.38852.7823-0.1496-0.1760.2662-0.03260.08240.0892-0.2368-0.12740.06720.02520.0171-0.01760.0161-0.01580.031523.688637.82945.7923
144.68542.3511.011512.21843.14083.62680.0120.06250.0846-0.297-0.02040.5814-0.1427-0.56790.00840.04840.0099-0.01470.11870.02760.035116.701732.0646-1.5234
156.0354-0.78031.311812.3279-0.0926.6962-0.0671-0.1195-0.2114-0.25240.03610.35140.1178-0.13840.03090.0331-0.0224-0.00870.06630.00950.051913.654518.2763-2.2521
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1046 - 1067
2X-RAY DIFFRACTION2A1068 - 1077
3X-RAY DIFFRACTION3A1078 - 1097
4X-RAY DIFFRACTION4A1098 - 1111
5X-RAY DIFFRACTION5A1112 - 1125
6X-RAY DIFFRACTION6A1126 - 1143
7X-RAY DIFFRACTION7A1144 - 1148
8X-RAY DIFFRACTION8A1149 - 1161
9X-RAY DIFFRACTION9B1046 - 1056
10X-RAY DIFFRACTION10B1057 - 1071
11X-RAY DIFFRACTION11B1072 - 1101
12X-RAY DIFFRACTION12B1102 - 1121
13X-RAY DIFFRACTION13B1122 - 1141
14X-RAY DIFFRACTION14B1142 - 1151
15X-RAY DIFFRACTION15B1152 - 1161

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