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- PDB-5o1b: p53 cancer mutant Y220C in complex with compound MB84 -

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Basic information

Entry
Database: PDB / ID: 5o1b
Titlep53 cancer mutant Y220C in complex with compound MB84
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-9H2 / Cellular tumor antigen p53
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.43 Å
AuthorsJoerger, A.C. / Bauer, M.R. / Baud, M.G.J. / 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 1.1Jan 17, 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)50,44310
Polymers49,0622
Non-polymers1,3818
Water8,323462
1
A: Cellular tumor antigen p53
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,2215
Polymers24,5311
Non-polymers6914
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Cellular tumor antigen p53
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,2215
Polymers24,5311
Non-polymers6914
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)65.152, 71.166, 105.344
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-9H2 / 6-(hydroxymethyl)-2,4-bis(iodanyl)-3-pyrrol-1-yl-phenol


Mass: 441.004 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C11H9I2NO2
#4: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 462 / 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: Mar 9, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97625 Å / Relative weight: 1
ReflectionResolution: 1.43→29.5 Å / Num. obs: 89897 / % possible obs: 98.8 % / Redundancy: 6.5 % / Biso Wilson estimate: 11.6 Å2 / Rmerge(I) obs: 0.05 / Net I/σ(I): 19
Reflection shellResolution: 1.43→1.51 Å / Redundancy: 5.9 % / Rmerge(I) obs: 0.388 / Mean I/σ(I) obs: 4.9 / % possible all: 96.7

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Processing

SoftwareName: PHENIX / Version: (1.10.1_2155: ???) / Classification: refinement
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 2j1x

2j1x


Resolution: 1.43→28.515 Å / SU ML: 0.11 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 17.45
RfactorNum. reflection% reflectionSelection details
Rfree0.1743 4421 4.92 %5
Rwork0.1505 ---
obs0.1517 89795 98.63 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.43→28.515 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3034 0 58 462 3554
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0053255
X-RAY DIFFRACTIONf_angle_d0.7834436
X-RAY DIFFRACTIONf_dihedral_angle_d16.0831225
X-RAY DIFFRACTIONf_chiral_restr0.082487
X-RAY DIFFRACTIONf_plane_restr0.006582
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.43-1.44620.2381250.19852701X-RAY DIFFRACTION94
1.4462-1.46330.21781590.17962699X-RAY DIFFRACTION96
1.4633-1.48110.23691370.17062789X-RAY DIFFRACTION97
1.4811-1.49990.1691240.15882796X-RAY DIFFRACTION98
1.4999-1.51960.16761560.15132788X-RAY DIFFRACTION98
1.5196-1.54040.19631490.14582769X-RAY DIFFRACTION98
1.5404-1.56240.18361320.14622848X-RAY DIFFRACTION99
1.5624-1.58570.2041540.14482790X-RAY DIFFRACTION98
1.5857-1.61050.17131390.14162842X-RAY DIFFRACTION99
1.6105-1.63690.15261430.1352795X-RAY DIFFRACTION99
1.6369-1.66510.14031190.12982867X-RAY DIFFRACTION98
1.6651-1.69540.17581540.12822814X-RAY DIFFRACTION98
1.6954-1.7280.17541660.12932807X-RAY DIFFRACTION99
1.728-1.76330.15241460.12892852X-RAY DIFFRACTION99
1.7633-1.80160.15861490.12762807X-RAY DIFFRACTION99
1.8016-1.84350.18561830.12822808X-RAY DIFFRACTION99
1.8435-1.88960.15731600.14072817X-RAY DIFFRACTION99
1.8896-1.94070.18371430.13222862X-RAY DIFFRACTION99
1.9407-1.99780.1611490.13912879X-RAY DIFFRACTION99
1.9978-2.06220.16121330.13862868X-RAY DIFFRACTION99
2.0622-2.13590.18191730.14222828X-RAY DIFFRACTION99
2.1359-2.22140.18611620.13952871X-RAY DIFFRACTION99
2.2214-2.32250.15751410.14472874X-RAY DIFFRACTION100
2.3225-2.44490.17751410.15192907X-RAY DIFFRACTION99
2.4449-2.59790.17561460.16012909X-RAY DIFFRACTION100
2.5979-2.79840.19491600.15852877X-RAY DIFFRACTION100
2.7984-3.07970.16821450.15852920X-RAY DIFFRACTION99
3.0797-3.52460.17071470.15432917X-RAY DIFFRACTION99
3.5246-4.43790.17071460.14872969X-RAY DIFFRACTION99
4.4379-28.52020.1691400.1813104X-RAY DIFFRACTION99

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