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- PDB-8dc4: Crystal structure of p53 Y220C covalently bound to carbazole KG3 -

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Basic information

Entry
Database: PDB / ID: 8dc4
TitleCrystal structure of p53 Y220C covalently bound to carbazole KG3
ComponentsCellular tumor antigen p53P53
KeywordsCELL CYCLE / TP53 / tumor suppressor
Function / homology
Function and homology information


Loss of function of TP53 in cancer due to loss of tetramerization ability / Regulation of TP53 Expression / signal transduction by p53 class mediator / negative regulation of G1 to G0 transition / negative regulation of glucose catabolic process to lactate via pyruvate / Transcriptional activation of cell cycle inhibitor p21 / regulation of intrinsic apoptotic signaling pathway by p53 class mediator / Activation of NOXA and translocation to mitochondria / negative regulation of pentose-phosphate shunt / ATP-dependent DNA/DNA annealing activity ...Loss of function of TP53 in cancer due to loss of tetramerization ability / Regulation of TP53 Expression / signal transduction by p53 class mediator / negative regulation of G1 to G0 transition / negative regulation of glucose catabolic process to lactate via pyruvate / Transcriptional activation of cell cycle inhibitor p21 / regulation of intrinsic apoptotic signaling pathway by p53 class mediator / Activation of NOXA and translocation to mitochondria / negative regulation of pentose-phosphate shunt / ATP-dependent DNA/DNA annealing activity / negative regulation of helicase activity / regulation of cell cycle G2/M phase transition / intrinsic apoptotic signaling pathway in response to hypoxia / regulation of fibroblast apoptotic process / oxidative stress-induced premature senescence / oligodendrocyte apoptotic process / negative regulation of miRNA processing / positive regulation of thymocyte apoptotic process / glucose catabolic process to lactate via pyruvate / regulation of tissue remodeling / positive regulation of mitochondrial membrane permeability / negative regulation of mitophagy / positive regulation of programmed necrotic cell death / mRNA transcription / bone marrow development / circadian behavior / histone deacetylase regulator activity / regulation of mitochondrial membrane permeability involved in apoptotic process / RUNX3 regulates CDKN1A transcription / germ cell nucleus / regulation of DNA damage response, signal transduction by p53 class mediator / TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain / TP53 Regulates Transcription of Death Receptors and Ligands / Activation of PUMA and translocation to mitochondria / DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator / negative regulation of glial cell proliferation / Formation of Senescence-Associated Heterochromatin Foci (SAHF) / negative regulation of neuroblast proliferation / Regulation of TP53 Activity through Association with Co-factors / mitochondrial DNA repair / T cell lineage commitment / positive regulation of execution phase of apoptosis / negative regulation of DNA replication / ER overload response / B cell lineage commitment / thymocyte apoptotic process / TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain / positive regulation of cardiac muscle cell apoptotic process / TP53 Regulates Transcription of Caspase Activators and Caspases / T cell proliferation involved in immune response / cardiac septum morphogenesis / entrainment of circadian clock by photoperiod / PI5P Regulates TP53 Acetylation / Association of TriC/CCT with target proteins during biosynthesis / Zygotic genome activation (ZGA) / necroptotic process / rRNA transcription / positive regulation of release of cytochrome c from mitochondria / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / TFIID-class transcription factor complex binding / mitophagy / SUMOylation of transcription factors / negative regulation of telomere maintenance via telomerase / general transcription initiation factor binding / intrinsic apoptotic signaling pathway by p53 class mediator / Transcriptional Regulation by VENTX / response to X-ray / DNA damage response, signal transduction by p53 class mediator / replicative senescence / chromosome organization / neuroblast proliferation / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / cellular response to UV-C / : / hematopoietic stem cell differentiation / negative regulation of reactive oxygen species metabolic process / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / glial cell proliferation / embryonic organ development / positive regulation of RNA polymerase II transcription preinitiation complex assembly / Pyroptosis / cis-regulatory region sequence-specific DNA binding / hematopoietic progenitor cell differentiation / cellular response to glucose starvation / cellular response to actinomycin D / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / somitogenesis / type II interferon-mediated signaling pathway / positive regulation of intrinsic apoptotic signaling pathway / negative regulation of stem cell proliferation / core promoter sequence-specific DNA binding / gastrulation / negative regulation of fibroblast proliferation / MDM2/MDM4 family protein binding / cardiac muscle cell apoptotic process / transcription initiation-coupled chromatin remodeling / 14-3-3 protein binding / mitotic G1 DNA damage checkpoint signaling / Regulation of TP53 Activity through Acetylation / response to salt stress
Similarity search - Function
Cellular tumor antigen p53, transactivation domain 2 / Transactivation domain 2 / p53 transactivation domain / P53 transactivation motif / p53 family signature. / p53, tetramerisation domain / P53 tetramerisation motif / p53, DNA-binding domain / P53 DNA-binding domain / p53 tumour suppressor family ...Cellular tumor antigen p53, transactivation domain 2 / Transactivation domain 2 / p53 transactivation domain / P53 transactivation motif / p53 family signature. / p53, tetramerisation domain / P53 tetramerisation motif / p53, DNA-binding domain / P53 DNA-binding domain / p53 tumour suppressor family / p53-like tetramerisation domain superfamily / p53/RUNT-type transcription factor, DNA-binding domain superfamily / p53-like transcription factor, DNA-binding
Similarity search - Domain/homology
Chem-R3R / Cellular tumor antigen p53
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsGuiley, K.Z. / Shokat, K.M.
Funding support United States, 1items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI)DRG: 2399-20 United States
CitationJournal: Cancer Discov / Year: 2023
Title: A Small Molecule Reacts with the p53 Somatic Mutant Y220C to Rescue Wild-type Thermal Stability.
Authors: Guiley, K.Z. / Shokat, K.M.
History
DepositionJun 15, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 12, 2022Provider: repository / Type: Initial release
Revision 1.1Jan 18, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation.year
Revision 1.2Oct 25, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: Cellular tumor antigen p53
A: Cellular tumor antigen p53
C: Cellular tumor antigen p53
D: Cellular tumor antigen p53
hetero molecules


Theoretical massNumber of molelcules
Total (without water)100,77112
Polymers99,5044
Non-polymers1,2678
Water4,936274
1
B: Cellular tumor antigen p53
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,1933
Polymers24,8761
Non-polymers3172
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: Cellular tumor antigen p53
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,1933
Polymers24,8761
Non-polymers3172
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Cellular tumor antigen p53
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,1933
Polymers24,8761
Non-polymers3172
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Cellular tumor antigen p53
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,1933
Polymers24,8761
Non-polymers3172
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)68.560, 68.560, 220.212
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number144
Space group name H-MP31
Space group name HallP31
Symmetry operation#1: x,y,z
#2: -y,x-y,z+1/3
#3: -x+y,-x,z+2/3
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
d_1ens_1(chain "A" and (resid 93 through 105 or resid 107...
d_2ens_1(chain "B" and (resid 93 through 105 or resid 107...
d_3ens_1(chain "C" and (resid 93 through 105 or resid 107...
d_4ens_1(chain "D" and (resid 93 through 105 or resid 107...

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg label comp-IDEnd label comp-IDLabel asym-IDLabel seq-ID
d_11ens_1METGLYB1 - 13
d_12ens_1TYRASPB15 - 56
d_13ens_1THRARGB58 - 64
d_14ens_1ARGGLNB66 - 73
d_15ens_1HISHISB76
d_16ens_1THRARGB78 - 89
d_17ens_1SERGLYB91 - 134
d_18ens_1ASPTHRB136 - 138
d_19ens_1ILEMETB140 - 154
d_110ens_1ARGARGB156 - 157
d_111ens_1ILEILEB159 - 163
d_112ens_1LEUPHEB165 - 178
d_113ens_1VALLEUB180 - 197
d_21ens_1METGLYA1 - 13
d_22ens_1TYRASPA15 - 56
d_23ens_1THRARGA58 - 64
d_24ens_1ARGGLNA66 - 73
d_25ens_1HISHISA76
d_26ens_1THRARGA78 - 89
d_27ens_1SERGLYA91 - 134
d_28ens_1ASPTHRA136 - 138
d_29ens_1ILEMETA140 - 154
d_210ens_1ARGARGA156 - 157
d_211ens_1ILEILEA159 - 163
d_212ens_1LEUPHEA165 - 178
d_213ens_1VALLEUA180 - 197
d_31ens_1METGLYC1 - 13
d_32ens_1TYRASPC15 - 56
d_33ens_1THRARGC58 - 64
d_34ens_1ARGGLNC66 - 73
d_35ens_1HISHISC76
d_36ens_1THRARGC78 - 89
d_37ens_1SERGLYC91 - 134
d_38ens_1ASPTHRC136 - 138
d_39ens_1ILEMETC140 - 154
d_310ens_1ARGARGC156 - 157
d_311ens_1ILEILEC159 - 163
d_312ens_1LEUPHEC165 - 178
d_313ens_1VALLEUC180 - 197
d_41ens_1METGLYD1 - 13
d_42ens_1TYRASPD15 - 56
d_43ens_1THRARGD58 - 64
d_44ens_1ARGGLND66 - 73
d_45ens_1HISHISD76
d_46ens_1THRARGD78 - 89
d_47ens_1SERGLYD91 - 134
d_48ens_1ASPTHRD136 - 138
d_49ens_1ILEMETD140 - 154
d_410ens_1ARGARGD156 - 157
d_411ens_1ILEILED159 - 163
d_412ens_1LEUPHED165 - 178
d_413ens_1VALLEUD180 - 197

NCS oper:
IDCodeMatrixVector
1given(0.505668424023, -0.862096263441, 0.0330072341603), (-0.862474192754, -0.504221795607, 0.0435734743616), (-0.020921562556, -0.050501617747, -0.99850481963)33.0517310666, 55.9182238863, 76.3945926459
2given(0.497213449979, 0.865731447737, -0.0573397380542), (-0.867289404575, 0.497779529005, -0.00496278304425), (0.0242461104522, 0.0521977097545, 0.998342388775)-64.6384710925, 38.663293774, -38.9366667325
3given(0.999997205591, -0.00232266432926, -0.000440501009649), (-0.00232213445811, -0.999996584315, 0.00119960372633), (-0.000443285781821, -0.00119857747158, -0.999999183455)-34.138358762, 98.8708215924, 111.015329477

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Components

#1: Protein
Cellular tumor antigen p53 / P53 / Antigen NY-CO-13 / Phosphoprotein p53 / Tumor suppressor p53


Mass: 24876.016 Da / Num. of mol.: 4 / Mutation: Y220C
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TP53, P53 / Production host: Escherichia coli (E. coli) / References: UniProt: P04637
#2: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-R3R / 9-propanoyl-9H-carbazole-3-carbaldehyde, bound form


Mass: 251.280 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C16H13NO2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 274 / 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: 3 Å3/Da / Density % sol: 59.04 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7 / Details: 100 mM HEPES, 2.2M MgSO4

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Data collection

DiffractionMean temperature: 80 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.2.1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Dec 16, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.4→59.37 Å / Num. obs: 45347 / % possible obs: 100 % / Redundancy: 4.6 % / CC1/2: 0.959 / Net I/σ(I): 5
Reflection shellResolution: 2.4→2.486 Å / Num. unique obs: 6668 / CC1/2: 0.533

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Processing

Software
NameVersionClassification
Blu-Icedata collection
iMOSFLMdata reduction
Aimlessdata scaling
PHASERphasing
PHENIX1.20.1refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2J1X

2j1x


Resolution: 2.4→59.37 Å / Cross valid method: FREE R-VALUE / σ(F): 62.44 / Phase error: 26.3609
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2313 2292 5.06 %
Rwork0.1607 42994 -
obs0.1758 45286 99.98 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 32.28 Å2
Refinement stepCycle: LAST / Resolution: 2.4→59.37 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6164 0 80 274 6518
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01116634
X-RAY DIFFRACTIONf_angle_d1.07499077
X-RAY DIFFRACTIONf_chiral_restr0.053989
X-RAY DIFFRACTIONf_plane_restr0.00771195
X-RAY DIFFRACTIONf_dihedral_angle_d6.2902975
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2BX-RAY DIFFRACTIONTorsion NCS0.750820559226
ens_1d_3BX-RAY DIFFRACTIONTorsion NCS0.692458855417
ens_1d_4BX-RAY DIFFRACTIONTorsion NCS0.396923952737
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.4-2.450.30421560.28432726X-RAY DIFFRACTION94.52
2.45-2.510.44421540.27572645X-RAY DIFFRACTION94.5
2.51-2.570.32981760.26822627X-RAY DIFFRACTION93.72
2.57-2.640.28491260.25692749X-RAY DIFFRACTION95.62
2.64-2.720.30991600.25372674X-RAY DIFFRACTION94.35
2.72-2.810.37331380.22632660X-RAY DIFFRACTION95.07
2.81-2.910.35261440.22022712X-RAY DIFFRACTION94.92
2.91-3.020.23561220.20722670X-RAY DIFFRACTION95.63
3.02-3.160.29041260.1952703X-RAY DIFFRACTION95.55
3.16-3.330.29281380.18382674X-RAY DIFFRACTION95.02
3.33-3.540.21521380.16032710X-RAY DIFFRACTION95.15
3.54-3.810.21061440.14932731X-RAY DIFFRACTION94.99
3.81-4.190.19541300.13022671X-RAY DIFFRACTION95.29
4.2-4.80.18041400.1112685X-RAY DIFFRACTION95.04
4.8-6.040.16981500.11672670X-RAY DIFFRACTION94.68

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