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- PDB-6si2: p53 cancer mutant Y220S -

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Basic information

Entry
Database: PDB / ID: 6si2
Titlep53 cancer mutant Y220S
ComponentsCellular tumor antigen p53
KeywordsDNA BINDING PROTEIN / p53 / transcription factor / tumor suppressor / cancer therapy / oncogenic mutant / druggable surface crevice / protein misfolding / mutant p53 rescue / DNA-binding domain
Function / homology
Function and homology information


negative regulation of helicase activity / signal transduction by p53 class mediator / Loss of function of TP53 in cancer due to loss of tetramerization ability / Regulation of TP53 Expression / regulation of cell cycle G2/M phase transition / negative regulation of G1 to G0 transition / Transcriptional activation of cell cycle inhibitor p21 / negative regulation of pentose-phosphate shunt / Activation of NOXA and translocation to mitochondria / ATP-dependent DNA/DNA annealing activity ...negative regulation of helicase activity / signal transduction by p53 class mediator / Loss of function of TP53 in cancer due to loss of tetramerization ability / Regulation of TP53 Expression / regulation of cell cycle G2/M phase transition / negative regulation of G1 to G0 transition / Transcriptional activation of cell cycle inhibitor p21 / negative regulation of pentose-phosphate shunt / Activation of NOXA and translocation to mitochondria / ATP-dependent DNA/DNA annealing activity / oligodendrocyte apoptotic process / positive regulation of thymocyte apoptotic process / oxidative stress-induced premature senescence / bone marrow development / cellular response to actinomycin D / circadian behavior / positive regulation of programmed necrotic cell death / RUNX3 regulates CDKN1A transcription / TP53 Regulates Transcription of Death Receptors and Ligands / Activation of PUMA and translocation to mitochondria / TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain / mRNA transcription / Regulation of TP53 Activity through Association with Co-factors / Urea cycle / ER overload response / hematopoietic stem cell differentiation / Formation of Senescence-Associated Heterochromatin Foci (SAHF) / TP53 Regulates Transcription of Caspase Activators and Caspases / intrinsic apoptotic signaling pathway by p53 class mediator / entrainment of circadian clock by photoperiod / Zygotic genome activation (ZGA) / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / PI5P Regulates TP53 Acetylation / positive regulation of release of cytochrome c from mitochondria / hematopoietic progenitor cell differentiation / Association of TriC/CCT with target proteins during biosynthesis / negative regulation of telomere maintenance via telomerase / SUMOylation of transcription factors / TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / Transcriptional Regulation by VENTX / TFIID-class transcription factor complex binding / replicative senescence / viral process / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / Pyroptosis / determination of adult lifespan / positive regulation of RNA polymerase II transcription preinitiation complex assembly / general transcription initiation factor binding / negative regulation of fibroblast proliferation / positive regulation of execution phase of apoptosis / type II interferon-mediated signaling pathway / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / cellular response to glucose starvation / core promoter sequence-specific DNA binding / cis-regulatory region sequence-specific DNA binding / Regulation of TP53 Activity through Acetylation / intrinsic apoptotic signaling pathway / mitotic G1 DNA damage checkpoint signaling / positive regulation of intrinsic apoptotic signaling pathway / response to gamma radiation / 14-3-3 protein binding / MDM2/MDM4 family protein binding / TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest / DNA damage response, signal transduction by p53 class mediator / protein phosphatase 2A binding / transcription initiation-coupled chromatin remodeling / molecular function activator activity / Regulation of PTEN gene transcription / tumor necrosis factor-mediated signaling pathway / cellular response to ionizing radiation / cellular response to xenobiotic stimulus / TP53 Regulates Metabolic Genes / TP53 Regulates Transcription of DNA Repair Genes / cellular response to gamma radiation / Regulation of NF-kappa B signaling / mRNA 3'-UTR binding / protein tetramerization / promoter-specific chromatin binding / Stabilization of p53 / molecular condensate scaffold activity / negative regulation of cell growth / nucleotide-excision repair / G2/M Checkpoints / receptor tyrosine kinase binding / Autodegradation of the E3 ubiquitin ligase COP1 / cellular senescence / PML body / PKR-mediated signaling / positive regulation of miRNA transcription / Oncogene Induced Senescence / DNA-binding transcription repressor activity, RNA polymerase II-specific / Regulation of TP53 Activity through Methylation / G2/M DNA damage checkpoint / DNA Damage/Telomere Stress Induced Senescence / Pre-NOTCH Transcription and Translation / transcription coactivator binding / positive regulation of reactive oxygen species metabolic process / intracellular protein localization / histone deacetylase binding
Similarity search - Function
Immunoglobulin-like - #720 / 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 ...Immunoglobulin-like - #720 / 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 / Immunoglobulin-like / Sandwich / Mainly Beta
Similarity search - Domain/homology
Cellular tumor antigen p53
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.5 Å
AuthorsJoerger, A.C. / Bauer, M.R. / Structural Genomics Consortium (SGC)
Funding support Germany, 1items
OrganizationGrant numberCountry
German Research FoundationJO 1473/1-1 Germany
CitationJournal: Acs Chem.Biol. / Year: 2020
Title: Targeting Cavity-Creating p53 Cancer Mutations with Small-Molecule Stabilizers: the Y220X Paradigm.
Authors: Bauer, M.R. / Kramer, A. / Settanni, G. / Jones, R.N. / Ni, X. / Khan Tareque, R. / Fersht, A.R. / Spencer, J. / Joerger, A.C.
History
DepositionAug 8, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 19, 2020Provider: repository / Type: Initial release
Revision 1.1Apr 1, 2020Group: 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 24, 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: Cellular tumor antigen p53
B: Cellular tumor antigen p53
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,4398
Polymers49,0292
Non-polymers4096
Water8,539474
1
A: Cellular tumor antigen p53
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,7044
Polymers24,5151
Non-polymers1903
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Cellular tumor antigen p53
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,7344
Polymers24,5151
Non-polymers2203
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)65.061, 71.216, 105.405
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 24514.746 Da / Num. of mol.: 2 / Fragment: DNA-binding domain / Mutation: M133L, V203A, Y220S, 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-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 474 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN

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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: 2.5 Å3/Da / Density % sol: 51 %
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.

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.97624 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Aug 8, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97624 Å / Relative weight: 1
ReflectionResolution: 1.5→29.6 Å / Num. obs: 78532 / % possible obs: 99.4 % / Redundancy: 4.7 % / CC1/2: 0.999 / Rmerge(I) obs: 0.06 / Net I/σ(I): 14.5
Reflection shellResolution: 1.5→1.58 Å / Redundancy: 4.6 % / Rmerge(I) obs: 0.53 / Mean I/σ(I) obs: 2.9 / Num. unique obs: 11369 / CC1/2: 0.875 / % possible all: 99.4

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Processing

Software
NameVersionClassification
PHENIX1.10.1_2155refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
SCALAdata scaling
PHENIXphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 2J1X

2j1x


Resolution: 1.5→29.59 Å / SU ML: 0.12 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 17.52
RfactorNum. reflection% reflection
Rfree0.1777 3993 5.09 %
Rwork0.1466 --
obs0.1482 78417 99.21 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 59.21 Å2 / Biso mean: 22.5537 Å2 / Biso min: 10.4 Å2
Refinement stepCycle: final / Resolution: 1.5→29.59 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3021 0 20 474 3515
Biso mean--37.57 34.2 -
Num. residues----393
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0053178
X-RAY DIFFRACTIONf_angle_d0.7734322
X-RAY DIFFRACTIONf_chiral_restr0.055478
X-RAY DIFFRACTIONf_plane_restr0.006571
X-RAY DIFFRACTIONf_dihedral_angle_d13.6541958
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.5-1.51770.21011540.1777252499
1.5177-1.53620.2251490.17312532100
1.5362-1.55560.19331530.1672251299
1.5556-1.57610.22551320.1582520100
1.5761-1.59770.18271280.1474256399
1.5977-1.62050.21031330.1422253399
1.6205-1.64470.17241180.13392578100
1.6447-1.67040.15731310.1271255699
1.6704-1.69780.16921300.1309254699
1.6978-1.7270.20061300.12862560100
1.727-1.75840.17331510.1356252699
1.7584-1.79220.16561350.12762561100
1.7922-1.82880.16831390.12422566100
1.8288-1.86860.15651360.12772540100
1.8686-1.9120.19331240.12592574100
1.912-1.95980.15761250.1243257599
1.9598-2.01280.16921290.1352255499
2.0128-2.0720.18111520.13512549100
2.072-2.13890.18671240.142600100
2.1389-2.21530.16681380.13932558100
2.2153-2.3040.15591310.1415259499
2.304-2.40880.17231370.1481255999
2.4088-2.53570.191330.1478258699
2.5357-2.69450.1951500.1557256399
2.6945-2.90240.15951440.1606256699
2.9024-3.19420.1651470.1594255698
3.1942-3.65560.16251270.1467262499
3.6556-4.60290.18991610.1429262199
4.6029-29.590.18911520.1681272898

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