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- PDB-5o1a: p53 cancer mutant Y220C in complex with compound MB240 -

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Basic information

Entry
Database: PDB / ID: 5o1a
Titlep53 cancer mutant Y220C in complex with compound MB240
ComponentsCellular tumor antigen p53P53
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 / glucose catabolic process to lactate via pyruvate / regulation of tissue remodeling / positive regulation of mitochondrial membrane permeability / negative regulation of mitophagy / positive regulation of programmed necrotic cell death / mRNA transcription / bone marrow development / circadian behavior / T cell proliferation involved in immune response / regulation of mitochondrial membrane permeability involved in apoptotic process / histone deacetylase regulator activity / RUNX3 regulates CDKN1A transcription / germ cell nucleus / 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 / negative regulation of neuroblast proliferation / negative regulation of glial cell proliferation / Formation of Senescence-Associated Heterochromatin Foci (SAHF) / Regulation of TP53 Activity through Association with Co-factors / positive regulation of execution phase of apoptosis / mitochondrial DNA repair / T cell lineage commitment / negative regulation of DNA replication / ER overload response / B cell lineage commitment / thymocyte apoptotic process / 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 / TP53 Regulates Transcription of Caspase Activators and Caspases / cardiac septum morphogenesis / entrainment of circadian clock by photoperiod / PI5P Regulates TP53 Acetylation / Association of TriC/CCT with target proteins during biosynthesis / Zygotic genome activation (ZGA) / necroptotic process / rRNA transcription / positive regulation of release of cytochrome c from mitochondria / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / TFIID-class transcription factor complex binding / mitophagy / negative regulation of telomere maintenance via telomerase / SUMOylation of transcription factors / intrinsic apoptotic signaling pathway by p53 class mediator / general transcription initiation factor binding / neuroblast proliferation / cellular response to actinomycin D / Transcriptional Regulation by VENTX / response to X-ray / DNA damage response, signal transduction by p53 class mediator / replicative senescence / chromosome organization / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / gastrulation / cellular response to UV-C / response to inorganic substance / hematopoietic stem cell differentiation / positive regulation of RNA polymerase II transcription preinitiation complex assembly / negative regulation of reactive oxygen species metabolic process / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / MDM2/MDM4 family protein binding / embryonic organ development / glial cell proliferation / Pyroptosis / cis-regulatory region sequence-specific DNA binding / hematopoietic progenitor cell differentiation / cellular response to glucose starvation / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / somitogenesis / type II interferon-mediated signaling pathway / DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest / positive regulation of intrinsic apoptotic signaling pathway / negative regulation of stem cell proliferation / core promoter sequence-specific DNA binding / negative regulation of fibroblast proliferation / response to salt stress / cardiac muscle cell apoptotic process / transcription initiation-coupled chromatin remodeling / mitotic G1 DNA damage checkpoint signaling / 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-9H5 / Cellular tumor antigen p53
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.44 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

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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)50,3597
Polymers49,0622
Non-polymers1,2975
Water7,566420
1
A: Cellular tumor antigen p53
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,1333
Polymers24,5311
Non-polymers6032
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Cellular tumor antigen p53
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,2254
Polymers24,5311
Non-polymers6953
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)65.156, 71.087, 105.264
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 / 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
Details: DNA-binding domain / 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-9H5 / [3,5-bis(iodanyl)-2-oxidanyl-4-pyrrol-1-yl-phenyl]-(4-methylpiperazin-1-yl)methanone


Mass: 537.134 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H17I2N3O2
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


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


Mass: 18.015 Da / Num. of mol.: 420 / 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: I04 / Wavelength: 0.97949 Å
DetectorType: DECTRIS PILATUS3 R CdTe 300K-W / Detector: PIXEL / Date: May 26, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97949 Å / Relative weight: 1
ReflectionResolution: 1.44→29.5 Å / Num. obs: 87871 / % possible obs: 98.8 % / Redundancy: 4.8 % / Biso Wilson estimate: 13.4 Å2 / Rmerge(I) obs: 0.052 / Net I/σ(I): 14.3
Reflection shellResolution: 1.44→1.52 Å / Redundancy: 4.8 % / Rmerge(I) obs: 0.46 / Mean I/σ(I) obs: 3.4 / % possible all: 99

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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: 1.44→29.456 Å / SU ML: 0.11 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 17.42 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.1783 4387 5 %random
Rwork0.1484 ---
obs0.1499 87765 98.6 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.44→29.456 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3021 0 54 420 3495
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0053263
X-RAY DIFFRACTIONf_angle_d0.8134475
X-RAY DIFFRACTIONf_dihedral_angle_d13.9741238
X-RAY DIFFRACTIONf_chiral_restr0.083492
X-RAY DIFFRACTIONf_plane_restr0.007592
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.44-1.45640.23951250.19552750X-RAY DIFFRACTION98
1.4564-1.47350.24041470.17782739X-RAY DIFFRACTION99
1.4735-1.49150.19321490.16482734X-RAY DIFFRACTION99
1.4915-1.51030.1811630.15652769X-RAY DIFFRACTION99
1.5103-1.53020.18111100.15532785X-RAY DIFFRACTION99
1.5302-1.55120.21531300.15432823X-RAY DIFFRACTION99
1.5512-1.57330.22351490.14812693X-RAY DIFFRACTION99
1.5733-1.59680.18951670.14992776X-RAY DIFFRACTION99
1.5968-1.62180.2121550.13992737X-RAY DIFFRACTION99
1.6218-1.64840.17691520.13752751X-RAY DIFFRACTION99
1.6484-1.67680.18751390.12772800X-RAY DIFFRACTION100
1.6768-1.70730.1861540.13042737X-RAY DIFFRACTION99
1.7073-1.74010.17311560.12942770X-RAY DIFFRACTION99
1.7401-1.77560.15941530.1252749X-RAY DIFFRACTION99
1.7756-1.81420.16741630.12012796X-RAY DIFFRACTION99
1.8142-1.85640.15931640.12582745X-RAY DIFFRACTION99
1.8564-1.90280.16661520.12982785X-RAY DIFFRACTION99
1.9028-1.95430.19131480.12992772X-RAY DIFFRACTION99
1.9543-2.01180.15061370.13162786X-RAY DIFFRACTION99
2.0118-2.07670.16591320.13312778X-RAY DIFFRACTION99
2.0767-2.15090.18611740.14052773X-RAY DIFFRACTION99
2.1509-2.2370.18321480.13542777X-RAY DIFFRACTION99
2.237-2.33870.17281360.14332797X-RAY DIFFRACTION98
2.3387-2.4620.1621400.15022784X-RAY DIFFRACTION98
2.462-2.61610.1951510.15532782X-RAY DIFFRACTION98
2.6161-2.8180.19851430.15782801X-RAY DIFFRACTION98
2.818-3.10130.1711400.15882802X-RAY DIFFRACTION97
3.1013-3.54940.18341410.15252767X-RAY DIFFRACTION97
3.5494-4.46940.16011360.15152851X-RAY DIFFRACTION98
4.4694-29.46190.17531330.17282969X-RAY DIFFRACTION97

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