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- PDB-6shz: p53 cancer mutant Y220C -

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Basic information

Entry
Database: PDB / ID: 6shz
Titlep53 cancer mutant Y220C
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 / 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 / negative regulation of pentose-phosphate shunt / ATP-dependent DNA/DNA annealing activity ...negative regulation of helicase 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 / negative regulation of pentose-phosphate shunt / ATP-dependent DNA/DNA annealing activity / Activation of NOXA and translocation to mitochondria / regulation of cell cycle G2/M phase transition / regulation of fibroblast apoptotic process / oligodendrocyte apoptotic process / negative regulation of miRNA processing / intrinsic apoptotic signaling pathway in response to hypoxia / positive regulation of thymocyte apoptotic process / oxidative stress-induced premature senescence / regulation of tissue remodeling / positive regulation of mitochondrial membrane permeability / mRNA transcription / bone marrow development / positive regulation of programmed necrotic cell death / circadian behavior / T cell proliferation involved in immune response / regulation of mitochondrial membrane permeability involved in apoptotic process / germ cell nucleus / RUNX3 regulates CDKN1A transcription / glucose catabolic process to lactate via pyruvate / 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 / regulation of DNA damage response, signal transduction by p53 class mediator / histone deacetylase regulator activity / negative regulation of glial cell proliferation / Regulation of TP53 Activity through Association with Co-factors / negative regulation of neuroblast proliferation / mitochondrial DNA repair / T cell lineage commitment / Formation of Senescence-Associated Heterochromatin Foci (SAHF) / ER overload response / thymocyte apoptotic process / B cell lineage commitment / TP53 Regulates Transcription of Caspase Activators and Caspases / cardiac septum morphogenesis / negative regulation of mitophagy / negative regulation of DNA replication / entrainment of circadian clock by photoperiod / negative regulation of telomere maintenance via telomerase / Zygotic genome activation (ZGA) / positive regulation of release of cytochrome c from mitochondria / PI5P Regulates TP53 Acetylation / Association of TriC/CCT with target proteins during biosynthesis / necroptotic process / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / TFIID-class transcription factor complex binding / 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 by p53 class mediator / negative regulation of reactive oxygen species metabolic process / rRNA transcription / Transcriptional Regulation by VENTX / cellular response to UV-C / replicative senescence / general transcription initiation factor binding / cellular response to actinomycin D / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / positive regulation of RNA polymerase II transcription preinitiation complex assembly / positive regulation of execution phase of apoptosis / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / neuroblast proliferation / Pyroptosis / viral process / hematopoietic stem cell differentiation / response to X-ray / embryonic organ development / chromosome organization / type II interferon-mediated signaling pathway / somitogenesis / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / hematopoietic progenitor cell differentiation / glial cell proliferation / negative regulation of fibroblast proliferation / positive regulation of cardiac muscle cell apoptotic process / core promoter sequence-specific DNA binding / negative regulation of stem cell proliferation / cellular response to glucose starvation / mitophagy / cis-regulatory region sequence-specific DNA binding / positive regulation of intrinsic apoptotic signaling pathway / Regulation of TP53 Activity through Acetylation / gastrulation / response to salt stress / 14-3-3 protein binding / mitotic G1 DNA damage checkpoint signaling / negative regulation of proteolysis / MDM2/MDM4 family protein binding / cardiac muscle cell apoptotic process / transcription repressor complex / intrinsic apoptotic signaling pathway
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 / 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: 1.24 Å
AuthorsJoerger, A.C. / Structural Genomics Consortium (SGC)
Funding support Germany, 1items
OrganizationGrant numberCountry
German Research FoundationJO 1473/1-1 Germany
Citation
Journal: 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.
#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.
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

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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)49,2067
Polymers48,8592
Non-polymers3475
Water9,242513
1
A: Cellular tumor antigen p53
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,6194
Polymers24,4301
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)24,5873
Polymers24,4301
Non-polymers1582
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)65.182, 71.154, 105.397
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: 24429.707 Da / Num. of mol.: 2 / Fragment: DNA-binding domain / 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-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#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.: 513 / 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: 50.82 %
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 PILATUS3 S 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: 1.24→58.973 Å / Num. obs: 135992 / % possible obs: 98 % / Redundancy: 5.5 % / Biso Wilson estimate: 11.97 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.053 / Net I/σ(I): 15.6
Reflection shellResolution: 1.24→1.31 Å / Redundancy: 5.5 % / Rmerge(I) obs: 0.582 / Mean I/σ(I) obs: 3.1 / Num. unique obs: 19284 / CC1/2: 0.887 / % possible all: 96.2

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Processing

Software
NameVersionClassification
PHENIX1.10.1_2155refinement
SCALA3.3.22data scaling
XDSdata reduction
PHENIXphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 2J1X

2j1x


Resolution: 1.24→29.487 Å / SU ML: 0.1 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 16.72 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1725 6936 5.11 %
Rwork0.1512 128882 -
obs0.1523 135818 97.7 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 56.18 Å2 / Biso mean: 18.5018 Å2 / Biso min: 7.95 Å2
Refinement stepCycle: final / Resolution: 1.24→29.487 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3043 0 16 513 3572
Biso mean--27.75 29.37 -
Num. residues----395
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0053271
X-RAY DIFFRACTIONf_angle_d0.8054467
X-RAY DIFFRACTIONf_chiral_restr0.085497
X-RAY DIFFRACTIONf_plane_restr0.007594
X-RAY DIFFRACTIONf_dihedral_angle_d17.3981247
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.24-1.25410.2492340.2312413995
1.2541-1.26880.22742210.2145415096
1.2688-1.28430.26452450.2069416696
1.2843-1.30060.20062350.1944417796
1.3006-1.31770.19392250.1813415896
1.3177-1.33570.19522360.1712418997
1.3357-1.35480.18032420.1665416897
1.3548-1.3750.18232090.1619426297
1.375-1.39650.21112190.1578423497
1.3965-1.41940.17142610.1537421297
1.4194-1.44390.17622410.15423597
1.4439-1.47020.15532000.1367423597
1.4702-1.49840.16922020.1388426697
1.4984-1.5290.14572360.1337430098
1.529-1.56230.17352500.1314421597
1.5623-1.59860.16632290.1264430398
1.5986-1.63860.14892470.1264425798
1.6386-1.68290.14782250.1226427998
1.6829-1.73240.16032260.1282433598
1.7324-1.78830.15722270.1319435499
1.7883-1.85220.16352430.1338435199
1.8522-1.92640.16942190.1392435799
1.9264-2.0140.15492130.1421436199
2.014-2.12020.16842400.1425437799
2.1202-2.2530.16252360.1441438199
2.253-2.42680.16712220.1544442799
2.4268-2.67090.17582260.1641441899
2.6709-3.0570.1862420.165443299
3.057-3.85020.16832440.1548450299
3.8502-29.4870.17492410.1543464299

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