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- PDB-8cg7: Structure of p53 cancer mutant Y220C with arylation at Cys182 and... -

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Basic information

Entry
Database: PDB / ID: 8cg7
TitleStructure of p53 cancer mutant Y220C with arylation at Cys182 and Cys277
ComponentsCellular tumor antigen p53P53
KeywordsTRANSCRIPTION / p53 cancer mutation / protein stability / covalent modification / Cys-arylation
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 / T cell proliferation involved in immune response / regulation of mitochondrial membrane permeability involved in apoptotic process / histone deacetylase regulator activity / 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 neuroblast proliferation / negative regulation of glial cell proliferation / Formation of Senescence-Associated Heterochromatin Foci (SAHF) / Regulation of TP53 Activity through Association with Co-factors / positive regulation of execution phase of apoptosis / mitochondrial DNA repair / T cell lineage commitment / negative regulation of DNA replication / ER overload response / B cell lineage commitment / thymocyte apoptotic process / positive regulation of cardiac muscle cell apoptotic process / TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain / TP53 Regulates Transcription of Caspase Activators and Caspases / 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 / negative regulation of telomere maintenance via telomerase / SUMOylation of transcription factors / intrinsic apoptotic signaling pathway by p53 class mediator / general transcription initiation factor binding / neuroblast proliferation / cellular response to actinomycin D / Transcriptional Regulation by VENTX / response to X-ray / DNA damage response, signal transduction by p53 class mediator / replicative senescence / chromosome organization / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / gastrulation / cellular response to UV-C / response to inorganic substance / hematopoietic stem cell differentiation / positive regulation of RNA polymerase II transcription preinitiation complex assembly / negative regulation of reactive oxygen species metabolic process / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / MDM2/MDM4 family protein binding / embryonic organ development / glial cell proliferation / Pyroptosis / cis-regulatory region sequence-specific DNA binding / hematopoietic progenitor cell differentiation / cellular response to glucose starvation / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / somitogenesis / type II interferon-mediated signaling pathway / DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest / positive regulation of intrinsic apoptotic signaling pathway / negative regulation of stem cell proliferation / core promoter sequence-specific DNA binding / negative regulation of fibroblast proliferation / response to salt stress / cardiac muscle cell apoptotic process / transcription initiation-coupled chromatin remodeling / mitotic G1 DNA damage checkpoint signaling / Regulation of TP53 Activity through Acetylation
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
Cellular tumor antigen p53
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.53 Å
AuthorsBalourdas, D.I. / Pichon, M.M. / Baud, M.G.J. / Knapp, S. / Joerger, A.C. / Structural Genomics Consortium (SGC)
Funding support Germany, 1items
OrganizationGrant numberCountry
German Research Foundation (DFG)JO 1473/1-3 Germany
CitationJournal: Bioconjug.Chem. / Year: 2023
Title: Structure-Reactivity Studies of 2-Sulfonylpyrimidines Allow Selective Protein Arylation.
Authors: Pichon, M.M. / Drelinkiewicz, D. / Lozano, D. / Moraru, R. / Hayward, L.J. / Jones, M. / McCoy, M.A. / Allstrum-Graves, S. / Balourdas, D.I. / Joerger, A.C. / Whitby, R.J. / Goldup, S.M. / ...Authors: Pichon, M.M. / Drelinkiewicz, D. / Lozano, D. / Moraru, R. / Hayward, L.J. / Jones, M. / McCoy, M.A. / Allstrum-Graves, S. / Balourdas, D.I. / Joerger, A.C. / Whitby, R.J. / Goldup, S.M. / Wells, N. / Langley, G.J. / Herniman, J.M. / Baud, M.G.J.
History
DepositionFeb 3, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 13, 2023Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)50,0065
Polymers49,8142
Non-polymers1933
Water8,035446
1
A: Cellular tumor antigen p53
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,9722
Polymers24,9071
Non-polymers651
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Cellular tumor antigen p53
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,0343
Polymers24,9071
Non-polymers1272
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)64.881, 71.046, 104.887
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

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


Mass: 24906.750 Da / Num. of mol.: 2
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.: 2 / Source method: isolated from a natural source / Formula: Zn
#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: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 446 / 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: 2.42 Å3/Da / Density % sol: 49.25 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: Protein solution: 6 mg/ml in 25 mM phosphate buffer, pH 7.2, 0.5 mM TCEP. Crystallization buffer: 19% polyethylene glycol 4000, 100 mM Hepes, pH 7.0. For covalent modification, crystals were ...Details: Protein solution: 6 mg/ml in 25 mM phosphate buffer, pH 7.2, 0.5 mM TCEP. Crystallization buffer: 19% polyethylene glycol 4000, 100 mM Hepes, pH 7.0. For covalent modification, crystals were soaked for 4 hours in crystallization buffer complemented with 20% glycerol and 30 mM compound before flash freezing in liquid nitrogen.

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Dec 18, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.53→47.9 Å / Num. obs: 73231 / % possible obs: 99.4 % / Redundancy: 5.6 % / Biso Wilson estimate: 19.7439955321 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.046 / Rrim(I) all: 0.051 / Net I/σ(I): 17.6
Reflection shellResolution: 1.53→1.56 Å / Redundancy: 5.7 % / Rmerge(I) obs: 0.801 / Mean I/σ(I) obs: 2.3 / Num. unique obs: 3553 / CC1/2: 0.892 / Rrim(I) all: 0.88 / % possible all: 99.4

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Processing

Software
NameVersionClassification
PHENIX1.10.1_2155refinement
XDSdata reduction
Aimlessdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.53→47.9 Å / SU ML: 0.170405593508 / Cross valid method: FREE R-VALUE / σ(F): 1.33790829767 / Phase error: 20.1344847681
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.187197998613 3695 5.05748699699 %
Rwork0.157916814985 69365 -
obs0.159423360227 73060 99.0174154638 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 26.7721371098 Å2
Refinement stepCycle: LAST / Resolution: 1.53→47.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3062 0 6 446 3514
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.006090967309143241
X-RAY DIFFRACTIONf_angle_d0.7847505409514428
X-RAY DIFFRACTIONf_chiral_restr0.0532847103742489
X-RAY DIFFRACTIONf_plane_restr0.00603369146287587
X-RAY DIFFRACTIONf_dihedral_angle_d13.55670851171974
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.53-1.55010.3270444396241390.2464315295822615X-RAY DIFFRACTION98.8513998564
1.5501-1.57140.2494237643831300.2252006815132629X-RAY DIFFRACTION99.3876080692
1.5714-1.59380.2328220342411220.2059209084192665X-RAY DIFFRACTION99.0053285968
1.5938-1.61760.2420444201911230.1933923622132665X-RAY DIFFRACTION99.0760483298
1.6176-1.64290.2575426307381460.1889627099132622X-RAY DIFFRACTION99.4967649173
1.6429-1.66980.2452770143091420.1674039954272639X-RAY DIFFRACTION99.0032039872
1.6698-1.69860.2203446803221300.1622477041282648X-RAY DIFFRACTION98.3362831858
1.6986-1.72950.1939759169081450.1508913771782610X-RAY DIFFRACTION98.6041517538
1.7295-1.76280.2110763668321400.1377692121532643X-RAY DIFFRACTION99.2510699001
1.7628-1.79880.1972460227481420.1371813100632659X-RAY DIFFRACTION99.3262411348
1.7988-1.83790.1803869305611630.1371447342912634X-RAY DIFFRACTION99.5728017088
1.8379-1.88060.1967358814261350.1452976671622685X-RAY DIFFRACTION99.7171145686
1.8806-1.92770.1925029831321370.1475007013042681X-RAY DIFFRACTION99.7169143666
1.9277-1.97980.1727434816511450.1399387526412663X-RAY DIFFRACTION99.4686503719
1.9798-2.0380.1940469486041490.1416180261412663X-RAY DIFFRACTION99.7870830376
2.038-2.10380.1704178235581620.1433133933412644X-RAY DIFFRACTION99.4682736618
2.1038-2.1790.1936353701751550.1434971662112659X-RAY DIFFRACTION99.294283698
2.179-2.26630.1974519255031360.1427120768952687X-RAY DIFFRACTION99.5767195767
2.2663-2.36940.2009502637381410.1477701617892645X-RAY DIFFRACTION98.1677237491
2.3694-2.49430.1688617441821420.1549349353192652X-RAY DIFFRACTION97.8291316527
2.4943-2.65060.1980546837251320.1615273623562693X-RAY DIFFRACTION99.2970123023
2.6506-2.85520.1991237830541760.1639111210412660X-RAY DIFFRACTION99.1261796575
2.8552-3.14250.1777064977131220.1609096515222721X-RAY DIFFRACTION99.0247300592
3.1425-3.59710.1625642082351360.1545444008022737X-RAY DIFFRACTION99.0348155808
3.5971-4.53140.1683710809081560.1489569111172685X-RAY DIFFRACTION96.9624573379
4.5314-47.90.1835899371131490.1823426468522861X-RAY DIFFRACTION98.3338778177

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