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- PDB-5o1e: p53 cancer mutant Y220C im complex with compound MB577 -

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Basic information

Entry
Database: PDB / ID: 5o1e
Titlep53 cancer mutant Y220C im complex with compound MB577
ComponentsCellular tumor antigen p53
KeywordsDNA BINDING PROTEIN / p53 / tumor suppressor / cancer mutation / protein stabilization / small-molecule stabilizers / cancer therapy / molecular chaperones
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 / regulation of tissue remodeling / glucose catabolic process to lactate via pyruvate / 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 / germ cell nucleus / T cell lineage commitment / regulation of mitochondrial membrane permeability involved in apoptotic process / RUNX3 regulates CDKN1A transcription / 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 / B cell lineage commitment / thymocyte apoptotic process / negative regulation of glial cell proliferation / negative regulation of neuroblast proliferation / Regulation of TP53 Activity through Association with Co-factors / mitochondrial DNA repair / Formation of Senescence-Associated Heterochromatin Foci (SAHF) / TP53 Regulates Transcription of Caspase Activators and Caspases / ER overload response / positive regulation of release of cytochrome c from mitochondria / negative regulation of DNA replication / 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 / entrainment of circadian clock by photoperiod / cardiac septum morphogenesis / PI5P Regulates TP53 Acetylation / Association of TriC/CCT with target proteins during biosynthesis / necroptotic process / Zygotic genome activation (ZGA) / positive regulation of execution phase of apoptosis / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / TFIID-class transcription factor complex binding / rRNA transcription / negative regulation of telomere maintenance via telomerase / SUMOylation of transcription factors / intrinsic apoptotic signaling pathway by p53 class mediator / general transcription initiation factor binding / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / Transcriptional Regulation by VENTX / DNA damage response, signal transduction by p53 class mediator / response to X-ray / replicative senescence / Pyroptosis / mitophagy / cellular response to UV-C / positive regulation of RNA polymerase II transcription preinitiation complex assembly / neuroblast proliferation / 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 / somitogenesis / embryonic organ development / chromosome organization / T cell proliferation involved in immune response / type II interferon-mediated signaling pathway / glial cell proliferation / viral process / cis-regulatory region sequence-specific DNA binding / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / hematopoietic progenitor cell differentiation / cellular response to actinomycin D / positive regulation of intrinsic apoptotic signaling pathway / cellular response to glucose starvation / core promoter sequence-specific DNA binding / negative regulation of stem cell proliferation / mitotic G1 DNA damage checkpoint signaling / negative regulation of fibroblast proliferation / gastrulation / MDM2/MDM4 family protein binding / tumor necrosis factor-mediated signaling pathway / response to salt stress / cardiac muscle cell apoptotic process / 14-3-3 protein binding / Regulation of TP53 Activity through Acetylation
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
Chem-9GT / Cellular tumor antigen p53
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.3 Å
AuthorsJoerger, A.C. / Baud, M.G.J. / Bauer, M.R. / Fersht, A.R.
CitationJournal: Eur J Med Chem / Year: 2018
Title: Aminobenzothiazole derivatives stabilize the thermolabile p53 cancer mutant Y220C and show anticancer activity in p53-Y220C cell lines.
Authors: Baud, M.G.J. / Bauer, M.R. / Verduci, L. / Dingler, F.A. / Patel, K.J. / Horil Roy, D. / Joerger, A.C. / Fersht, A.R.
History
DepositionMay 18, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 9, 2018Provider: repository / Type: Initial release
Revision 1.1May 8, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
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)50,1478
Polymers49,0622
Non-polymers1,0856
Water7,278404
1
A: Cellular tumor antigen p53
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,9813
Polymers24,5311
Non-polymers4512
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Cellular tumor antigen p53
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,1665
Polymers24,5311
Non-polymers6354
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)65.078, 71.176, 105.185
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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: 24530.811 Da / Num. of mol.: 2 / Fragment: UNP residues 94-312 / 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-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-9GT / 3-iodanyl-2-oxidanyl-5-prop-2-enoxy-4-pyrrol-1-yl-benzoic acid


Mass: 385.154 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H12INO4
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 404 / Source method: isolated from a natural source / Formula: H2O

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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. Soaking ...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: 30 mM 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: 1.3→29.6 Å / Num. obs: 120220 / % possible obs: 99.8 % / Redundancy: 4.7 % / Rmerge(I) obs: 0.05 / Net I/σ(I): 13.7
Reflection shellResolution: 1.3→1.37 Å / Redundancy: 4.7 % / Rmerge(I) obs: 0.58 / Mean I/σ(I) obs: 2.7 / % possible all: 99.9

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Processing

SoftwareName: PHENIX / Version: (1.10.1_2155: ???) / Classification: refinement
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.3→29.474 Å / SU ML: 0.09 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 16.03
RfactorNum. reflection% reflection
Rfree0.1647 5956 4.96 %
Rwork0.1491 --
obs0.1499 120085 99.71 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.3→29.474 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3038 0 54 404 3496
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0053266
X-RAY DIFFRACTIONf_angle_d0.8414464
X-RAY DIFFRACTIONf_dihedral_angle_d15.381234
X-RAY DIFFRACTIONf_chiral_restr0.085488
X-RAY DIFFRACTIONf_plane_restr0.007591
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.3-1.31480.25522150.21493716X-RAY DIFFRACTION100
1.3148-1.33020.21771800.20363796X-RAY DIFFRACTION100
1.3302-1.34650.18742030.1993746X-RAY DIFFRACTION100
1.3465-1.36350.23951940.18613757X-RAY DIFFRACTION100
1.3635-1.38150.20221760.18593800X-RAY DIFFRACTION100
1.3815-1.40040.17941950.17453783X-RAY DIFFRACTION100
1.4004-1.42040.20551830.16243808X-RAY DIFFRACTION100
1.4204-1.44160.1852160.1623734X-RAY DIFFRACTION100
1.4416-1.46410.17091930.15053759X-RAY DIFFRACTION100
1.4641-1.48810.15391870.14243790X-RAY DIFFRACTION100
1.4881-1.51380.15962070.12993785X-RAY DIFFRACTION100
1.5138-1.54130.13471830.1263770X-RAY DIFFRACTION100
1.5413-1.57090.15692010.12563796X-RAY DIFFRACTION100
1.5709-1.6030.14751900.12673790X-RAY DIFFRACTION100
1.603-1.63790.17032030.12233768X-RAY DIFFRACTION100
1.6379-1.6760.14531890.11573816X-RAY DIFFRACTION100
1.676-1.71790.15592210.12073777X-RAY DIFFRACTION100
1.7179-1.76430.13381980.12093806X-RAY DIFFRACTION100
1.7643-1.81620.15782220.12393767X-RAY DIFFRACTION100
1.8162-1.87480.14412200.13153778X-RAY DIFFRACTION100
1.8748-1.94180.16742010.13393787X-RAY DIFFRACTION100
1.9418-2.01950.14631950.13933806X-RAY DIFFRACTION100
2.0195-2.11140.15052090.14063813X-RAY DIFFRACTION100
2.1114-2.22270.18442120.14223820X-RAY DIFFRACTION100
2.2227-2.36190.15741880.15143822X-RAY DIFFRACTION100
2.3619-2.54420.1651940.15463848X-RAY DIFFRACTION100
2.5442-2.80010.16822050.16083840X-RAY DIFFRACTION100
2.8001-3.20480.15291900.16113874X-RAY DIFFRACTION99
3.2048-4.03610.17162110.15193901X-RAY DIFFRACTION99
4.0361-29.48170.16611750.16034076X-RAY DIFFRACTION99

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