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- PDB-8a31: p53 cancer mutant Y220C in complex with iodophenol-based small-mo... -

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Basic information

Entry
Database: PDB / ID: 8a31
Titlep53 cancer mutant Y220C in complex with iodophenol-based small-molecule stabilizer JC694
ComponentsCellular tumor antigen p53
KeywordsTRANSCRIPTION / tumor suppressor p53 / cancer mutant / drug discovery / small-molecule stabilizer
Function / homology
Function and homology information


Loss of function of TP53 in cancer due to loss of tetramerization ability / Regulation of TP53 Expression / negative regulation of helicase activity / 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 ...Loss of function of TP53 in cancer due to loss of tetramerization ability / Regulation of TP53 Expression / negative regulation of helicase activity / 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 / intrinsic apoptotic signaling pathway in response to hypoxia / oligodendrocyte apoptotic process / negative regulation of miRNA processing / positive regulation of thymocyte apoptotic process / oxidative stress-induced premature senescence / regulation of tissue remodeling / glucose catabolic process to lactate via pyruvate / positive regulation of mitochondrial membrane permeability / positive regulation of programmed necrotic cell death / negative regulation of mitophagy / mRNA transcription / circadian behavior / bone marrow development / germ cell nucleus / regulation of mitochondrial membrane permeability involved in apoptotic process / regulation of DNA damage response, signal transduction by p53 class mediator / RUNX3 regulates CDKN1A transcription / 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 / : / histone deacetylase regulator activity / negative regulation of glial cell proliferation / Regulation of TP53 Activity through Association with Co-factors / negative regulation of neuroblast proliferation / T cell lineage commitment / mitochondrial DNA repair / Formation of Senescence-Associated Heterochromatin Foci (SAHF) / ER overload response / B cell lineage commitment / thymocyte apoptotic process / TP53 Regulates Transcription of Caspase Activators and Caspases / negative regulation of DNA replication / cardiac septum morphogenesis / entrainment of circadian clock by photoperiod / PI5P Regulates TP53 Acetylation / negative regulation of telomere maintenance via telomerase / necroptotic process / positive regulation of release of cytochrome c from mitochondria / Zygotic genome activation (ZGA) / Association of TriC/CCT with target proteins during biosynthesis / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / TFIID-class transcription factor complex binding / T cell proliferation involved in immune response / rRNA transcription / 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 / positive regulation of execution phase of apoptosis / Transcriptional Regulation by VENTX / general transcription initiation factor binding / replicative senescence / cellular response to actinomycin D / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / cellular response to UV-C / neuroblast proliferation / hematopoietic stem cell differentiation / positive regulation of RNA polymerase II transcription preinitiation complex assembly / response to X-ray / negative regulation of reactive oxygen species metabolic process / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / DNA damage response, signal transduction by p53 class mediator / chromosome organization / viral process / Pyroptosis / embryonic organ development / cis-regulatory region sequence-specific DNA binding / type II interferon-mediated signaling pathway / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / somitogenesis / glial cell proliferation / hematopoietic progenitor cell differentiation / core promoter sequence-specific DNA binding / negative regulation of stem cell proliferation / : / cellular response to glucose starvation / mitophagy / positive regulation of intrinsic apoptotic signaling pathway / negative regulation of fibroblast proliferation / positive regulation of cardiac muscle cell apoptotic process / tumor necrosis factor-mediated signaling pathway / mitotic G1 DNA damage checkpoint signaling / Regulation of TP53 Activity through Acetylation / gastrulation / MDM2/MDM4 family protein binding / response to salt stress / 14-3-3 protein binding
Similarity search - Function
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 ...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
Similarity search - Domain/homology
Chem-KV0 / Cellular tumor antigen p53
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.46 Å
AuthorsBalourdas, D.I. / Stephenson Clarke, J.R. / Baud, M.G.J. / Knapp, S. / Joerger, A.C. / Structural Genomics Consortium (SGC)
Funding support Germany, 1items
OrganizationGrant numberCountry
German Research Foundation (DFG)JO 1473/1-3 Germany
CitationJournal: Acs Pharmacol Transl Sci / Year: 2022
Title: Discovery of Nanomolar-Affinity Pharmacological Chaperones Stabilizing the Oncogenic p53 Mutant Y220C.
Authors: Stephenson Clarke, J.R. / Douglas, L.R. / Duriez, P.J. / Balourdas, D.I. / Joerger, A.C. / Khadiullina, R. / Bulatov, E. / Baud, M.G.J.
History
DepositionJun 6, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 30, 2022Provider: repository / Type: Initial release
Revision 1.1Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)50,2307
Polymers49,0622
Non-polymers1,1695
Water7,819434
1
A: Cellular tumor antigen p53
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,0693
Polymers24,5311
Non-polymers5382
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Cellular tumor antigen p53
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,1614
Polymers24,5311
Non-polymers6303
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)64.981, 71.063, 105.089
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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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: DNA-binding domain
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-KV0 / 4-(3-fluoranylpyrrol-1-yl)-3,5-bis(iodanyl)-2-oxidanyl-benzoic acid


Mass: 472.978 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C11H6FI2NO3 / Feature type: SUBJECT OF INVESTIGATION
#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.: 434 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.47 Å3/Da / Density % sol: 50.26 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: Protein solution: 5.7 mg/ml protein in 25 mM sodium phosphate, pH 7.2, 150 mm NaCl, 0.5 mM TCEP. Reservoir buffer: 100 mm HEPES, pH 7.2, 19% (w/v) polyethylene glycol 4000, 5 mm DTT. Soaking ...Details: Protein solution: 5.7 mg/ml protein in 25 mM sodium phosphate, pH 7.2, 150 mm NaCl, 0.5 mM TCEP. Reservoir buffer: 100 mm HEPES, pH 7.2, 19% (w/v) polyethylene glycol 4000, 5 mm DTT. Soaking buffer: 20 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 NaCl.

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.999998 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Dec 18, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.999998 Å / Relative weight: 1
ReflectionResolution: 1.46→49.5 Å / Num. obs: 84274 / % possible obs: 99.2 % / Redundancy: 5.6 % / Biso Wilson estimate: 14.3992113092 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.062 / Net I/σ(I): 12.9
Reflection shellResolution: 1.46→1.48 Å / Redundancy: 5.8 % / Rmerge(I) obs: 0.821 / Mean I/σ(I) obs: 2.3 / Num. unique obs: 4099 / CC1/2: 0.911 / % possible all: 98.2

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimlessdata scaling
PHENIXphasing
PHENIX1.10.1_2155refinement
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 6shz

6shz


Resolution: 1.46→47.9807 Å / SU ML: 0.120112289612 / Cross valid method: FREE R-VALUE / σ(F): 1.33787302829 / Phase error: 20.7665322381
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.190642504555 4200 4.99411407983 %
Rwork0.157258724081 79899 -
obs0.158944359505 84099 98.8434822467 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 21.1746285667 Å2
Refinement stepCycle: LAST / Resolution: 1.46→47.9807 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3033 0 44 434 3511
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00654036398983265
X-RAY DIFFRACTIONf_angle_d0.8780613841134465
X-RAY DIFFRACTIONf_chiral_restr0.0845719654955488
X-RAY DIFFRACTIONf_plane_restr0.00696013630109641
X-RAY DIFFRACTIONf_dihedral_angle_d16.57790146291251
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.46-1.47660.2359672332871290.2286351323362613X-RAY DIFFRACTION97.3375931842
1.4766-1.4940.2470307276381370.1971299737392582X-RAY DIFFRACTION98.7291212781
1.494-1.51220.2214469423931460.1891885300052639X-RAY DIFFRACTION97.5823405746
1.5122-1.53140.2000127628781410.1703615397672621X-RAY DIFFRACTION99.1741472172
1.5314-1.55150.2010023668471510.1669746660292601X-RAY DIFFRACTION97.9359430605
1.5515-1.57280.1966974574421380.1601803418542596X-RAY DIFFRACTION98.6647419704
1.5728-1.59520.1831451521791200.1582376733882667X-RAY DIFFRACTION98.7247608927
1.5952-1.6190.1942616108891390.1543967149662607X-RAY DIFFRACTION98.0364155659
1.619-1.64430.2240876441311230.1560040632382643X-RAY DIFFRACTION99.3534482759
1.6443-1.67130.1942579008611290.1507448648532663X-RAY DIFFRACTION98.7619384507
1.6713-1.70010.2006619617561070.1464675548762677X-RAY DIFFRACTION98.5835694051
1.7001-1.7310.1998109285891330.1442363674522601X-RAY DIFFRACTION98.0983135989
1.731-1.76430.1956677572251340.1429160900612682X-RAY DIFFRACTION99.5404736656
1.7643-1.80030.1723042144621410.1437652669622643X-RAY DIFFRACTION98.933901919
1.8003-1.83950.1706199367231360.1342816428292656X-RAY DIFFRACTION99.2181947406
1.8395-1.88230.1753557882581500.1402171530122657X-RAY DIFFRACTION99.1522430237
1.8823-1.92940.169071218561400.1365606782962669X-RAY DIFFRACTION99.398443029
1.9294-1.98150.1744381692541450.1373054715252658X-RAY DIFFRACTION99.2563739377
1.9815-2.03980.2057206782171550.1444000837742657X-RAY DIFFRACTION99.5750708215
2.0398-2.10570.1745658500751280.1460771906822671X-RAY DIFFRACTION99.3963068182
2.1057-2.18090.1497959353451280.1522486466092695X-RAY DIFFRACTION99.5767195767
2.1809-2.26830.1851789907561630.1436419106312665X-RAY DIFFRACTION99.6476391825
2.2683-2.37150.2020674839771530.1576424268552669X-RAY DIFFRACTION99.1218826835
2.3715-2.49650.2063451988961520.1569051061062649X-RAY DIFFRACTION97.9713186429
2.4965-2.65290.2082247535961640.1595330954132669X-RAY DIFFRACTION99.4383994384
2.6529-2.85770.1750740910351410.1645729663472718X-RAY DIFFRACTION99.8254189944
2.8577-3.14530.1936265757691280.1624767123312730X-RAY DIFFRACTION99.6165911467
3.1453-3.60020.1742849336311570.1575109051872726X-RAY DIFFRACTION99.2085340674
3.6002-4.53540.1891348749341300.1541711533562743X-RAY DIFFRACTION98.0880846705
4.5354-47.98070.2085262160041620.1809628506812832X-RAY DIFFRACTION97.6516634051

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