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- PDB-6gga: p53 cancer mutant Y220C in complex with small-molecule stabilizer... -

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Basic information

Entry
Database: PDB / ID: 6gga
Titlep53 cancer mutant Y220C in complex with small-molecule stabilizer PK9284
ComponentsCellular tumor antigen p53P53
KeywordsDNA BINDING PROTEIN / p53 / transcription factor / tumor supressor / cancer therapy / oncogenic mutant / protein misfolding / small-molecule stabilizer / molecular chaperone
Function / homology
Function and homology information


Regulation of TP53 Expression / G2/M Checkpoints / Autodegradation of the E3 ubiquitin ligase COP1 / DNA Damage/Telomere Stress Induced Senescence / Oncogene Induced Senescence / Formation of Senescence-Associated Heterochromatin Foci (SAHF) / Oxidative Stress Induced Senescence / Regulation of TP53 Degradation / Pre-NOTCH Transcription and Translation / G2/M DNA damage checkpoint ...Regulation of TP53 Expression / G2/M Checkpoints / Autodegradation of the E3 ubiquitin ligase COP1 / DNA Damage/Telomere Stress Induced Senescence / Oncogene Induced Senescence / Formation of Senescence-Associated Heterochromatin Foci (SAHF) / Oxidative Stress Induced Senescence / Regulation of TP53 Degradation / Pre-NOTCH Transcription and Translation / G2/M DNA damage checkpoint / Activation of PUMA and translocation to mitochondria / Activation of NOXA and translocation to mitochondria / Regulation of TP53 Activity through Phosphorylation / TP53 Regulates Metabolic Genes / Regulation of TP53 Activity through Acetylation / PI5P Regulates TP53 Acetylation / Regulation of TP53 Activity through Association with Co-factors / Association of TriC/CCT with target proteins during biosynthesis / SUMOylation of transcription factors / Stabilization of p53 / Regulation of PTEN gene transcription / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain / TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest / TP53 Regulates Transcription of Death Receptors and Ligands / TP53 Regulates Transcription of Caspase Activators and Caspases / TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / Transcriptional activation of cell cycle inhibitor p21 / Factors involved in megakaryocyte development and platelet production / TP53 Regulates Transcription of DNA Repair Genes / Interleukin-4 and Interleukin-13 signaling / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / Regulation of TP53 Activity through Methylation / Ub-specific processing proteases / RUNX3 regulates CDKN1A transcription / The role of GTSE1 in G2/M progression after G2 checkpoint / Ovarian tumor domain proteases / signal transduction by p53 class mediator / regulation of fibroblast apoptotic process / regulation of intrinsic apoptotic signaling pathway by p53 class mediator / positive regulation of programmed necrotic cell death / negative regulation of glucose catabolic process to lactate via pyruvate / oxidative stress-induced premature senescence / intrinsic apoptotic signaling pathway in response to hypoxia / core promoter sequence-specific DNA binding / negative regulation of mitophagy / oligodendrocyte apoptotic process / negative regulation of helicase activity / regulation of tissue remodeling / DNA strand renaturation / positive regulation of thymocyte apoptotic process / positive regulation of cell aging / bone marrow development / regulation of mitochondrial membrane permeability involved in apoptotic process / positive regulation of mitochondrial membrane permeability / circadian behavior / regulation of glycolytic process by positive regulation of transcription from RNA polymerase II promoter / T cell lineage commitment / histone deacetylase regulator activity / chromatin assembly / regulation of DNA damage response, signal transduction by p53 class mediator / negative regulation of neuroblast proliferation / positive regulation of execution phase of apoptosis / positive regulation of transcription from RNA polymerase II promoter in response to endoplasmic reticulum stress / regulation of cell cycle G2/M phase transition / regulation of cellular senescence / mRNA transcription / mitotic cell cycle arrest / B cell lineage commitment / TFIID-class transcription factor complex binding / positive regulation of histone deacetylation / MDM2/MDM4 family protein binding / mitochondrial DNA repair / negative regulation of DNA replication / entrainment of circadian clock by photoperiod / hematopoietic stem cell differentiation / positive regulation of cardiac muscle cell apoptotic process / rRNA transcription / positive regulation of transcription from RNA polymerase II promoter in response to hypoxia / cellular response to actinomycin D / ER overload response / T cell proliferation involved in immune response / intrinsic apoptotic signaling pathway by p53 class mediator / cardiac septum morphogenesis / RNA polymerase II preinitiation complex assembly / embryonic organ development / necroptotic process / somitogenesis / DNA damage response, signal transduction by p53 class mediator / response to salt stress / gastrulation / cellular protein localization / regulation of mitochondrial membrane permeability / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / cellular response to UV-C / negative regulation of fibroblast proliferation / positive regulation of protein oligomerization / DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator / positive regulation of release of cytochrome c from mitochondria
p53 tumour suppressor family / p53 transactivation domain / p53-like transcription factor, DNA-binding / p53 family signature. / p53, tetramerisation domain / Transactivation domain 2 / p53, DNA-binding domain / P53 transactivation motif / P53 tetramerisation motif / P53 DNA-binding domain ...p53 tumour suppressor family / p53 transactivation domain / p53-like transcription factor, DNA-binding / p53 family signature. / p53, tetramerisation domain / Transactivation domain 2 / p53, DNA-binding domain / P53 transactivation motif / P53 tetramerisation motif / P53 DNA-binding domain / Cellular tumor antigen p53, transactivation domain 2 / p53-like tetramerisation domain superfamily / p53/RUNT-type transcription factor, DNA-binding domain superfamily
Cellular tumor antigen p53
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.55000123008 Å
AuthorsJoerger, A.C. / Bauer, M.R.
Funding support Germany, 1items
OrganizationGrant numberCountry
German Research FoundationJO 1473/1-1 Germany
Citation
Journal: to be published
Title: A structure-guided molecular chaperone approach for restoring the transcriptional activity of the p53 cancer mutant Y220C
Authors: Jones, R.N. / Bauer, M.R. / Springett, B. / Dingler, F.A. / Verduci, L. / Patel, K.J. / Fersht, A.R. / Joerger, A.C. / Spencer, J.
#1: Journal: Proc. Natl. Acad. Sci. U.S.A. / Year: 2006
Title: Structural basis for understanding oncogenic p53 mutations and designing rescue drugs.
Authors: Joerger, A.C. / Ang, H.C. / Fersht, A.R.
Validation Report
SummaryFull reportAbout validation report
History
DepositionMay 3, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 22, 2019Provider: 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)49,8296
Polymers49,0622
Non-polymers7674
Water6,720373
1
A: Cellular tumor antigen p53
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,9143
Polymers24,5311
Non-polymers3842
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Cellular tumor antigen p53
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,9143
Polymers24,5311
Non-polymers3842
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
γ
α
β
Length a, b, c (Å)65.001, 71.187, 105.138
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab

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Components

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


Mass: 24530.811 Da / Num. of mol.: 2 / Mutation: M133L, V203A, Y220C, N239Y, N268D
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-EY2 / (7-bromanyl-9-ethyl-carbazol-3-yl)methyl-methyl-azanium


Mass: 318.232 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H18BrN2
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn / Zinc
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 373 / Source method: isolated from a natural source / Formula: H2O / Water

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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: 2.73 Å3/Da / Density % sol: 54.97 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: Protein solution: 6 mg/ml protein in 25 mM sodium phosphate, ph 7.2, 150 mm KCl, 5 mm DTT. Reservoir buffer: 100 mm HEPES, pH 7.2, 19% (w/v) polyethylene glycol 4000, 5 mm DTT. Soaking buffer: Saturated solution of compound in 100 mm HEPES, ph 7.2, 10 mM sodium phosphate, ph 7.2, 19% (w/v) polyethylene glycol 4000, 20 % (v/v) glycerol, 150 mm KCl.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.97625 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: May 9, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97625 Å / Relative weight: 1
ReflectionResolution: 1.55→29.6 Å / Num. obs: 71228 / % possible obs: 99.8 % / Redundancy: 4.4 % / Biso Wilson estimate: 21.1678580024 Å2 / Rmerge(I) obs: 0.036 / Net I/σ(I): 17.9
Reflection shellResolution: 1.55→1.63 Å / Redundancy: 4.3 % / Rmerge(I) obs: 0.47 / Mean I/σ(I) obs: 2.9 / % possible all: 99

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Processing

Software
NameVersionClassification
PHENIX1.10.1_2155refinement
PDB_EXTRACT3.24data extraction
XDSdata reduction
SCALAdata scaling
PHENIXphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 2J1X
Resolution: 1.55000123008→29.564987517 Å / SU ML: 0.146678858905 / Cross valid method: THROUGHOUT / σ(F): 1.34316576257 / Phase error: 22.0536519888
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.199643751526 3593 5.05415670277 %
Rwork0.180571531816 67497 -
Obs0.181509113995 71090 99.5672208294 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 27.8531910821 Å2
Refinement stepCycle: LAST / Resolution: 1.55000123008→29.564987517 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3018 0 40 373 3431
Refine LS restraints

Refinement-ID: X-RAY DIFFRACTION

TypeDev idealNumber
f_bond_d0.006055204783413196
f_angle_d0.7929912249084369
f_chiral_restr0.0550784733397481
f_plane_restr0.0063263432361574
f_dihedral_angle_d11.29902684371948
LS refinement shell

Refinement-ID: X-RAY DIFFRACTION

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.55-1.57040.3037294328331490.255335693419251099.849793466
1.5704-1.59190.2569283980971380.255130330796256699.6682639145
1.5919-1.61460.2723663311141360.235656993963255499.7404523545
1.6146-1.63870.2498577899191380.224501580107258899.8534798535
1.6387-1.66440.2458571089711430.209676322383256899.7424576895
1.6644-1.69160.244448708021460.20752286649257499.8531571219
1.6916-1.72080.2441454051841410.208782727049255299.4828223125
1.7208-1.75210.208290825461290.200023352245257999.7789240973
1.7521-1.78580.2271379110241440.201063995504258799.5988329686
1.7858-1.82220.2639787304771540.185895305365253899.8516320475
1.8222-1.86180.2349190635081580.191219359474255699.6694821888
1.8618-1.90510.2301251858321390.179309675326259299.817251462
1.9051-1.95280.2162698162141340.174969090144259499.7440585009
1.9528-2.00560.1818756937891300.188837774612256999.7044698929
2.0056-2.06460.2358603566321260.185186668131261599.7815799054
2.0646-2.13120.1973985362891550.18334268734255799.5594713656
2.1312-2.20730.2143285700021450.179482658945260199.709513435
2.2073-2.29570.2211184407131200.181322323694263199.7823721436
2.2957-2.40010.2005411672441340.182888153347259699.8171846435
2.4001-2.52660.1984878517281360.187672634344261699.7462848858
2.5266-2.68480.1895718216731360.182476579303261499.6015936255
2.6848-2.89190.2216865394331440.182156654109259999.0968208092
2.8919-3.18270.2006884179891260.179488754735262799.2072072072
3.1827-3.64250.1811066308011440.167942664361266099.3269571378
3.6425-4.58640.1412454130811240.158401917799266998.7623762376
4.5864-29.57040.1882981231161240.174867569964278598.277027027

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