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- PDB-8a32: p53 cancer mutant Y220C in complex with iodophenol-based small-mo... -

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Basic information

Entry
Database: PDB / ID: 8a32
Titlep53 cancer mutant Y220C in complex with iodophenol-based small-molecule stabilizer JC769
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 / 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
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-KVA / Cellular tumor antigen p53
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.47 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)50,3298
Polymers49,0622
Non-polymers1,2676
Water7,927440
1
A: Cellular tumor antigen p53
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,1494
Polymers24,5311
Non-polymers6183
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Cellular tumor antigen p53
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,1794
Polymers24,5311
Non-polymers6483
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)65.119, 71.072, 105.315
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

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Protein , 1 types, 2 molecules AB

#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

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Non-polymers , 5 types, 446 molecules

#2: Chemical ChemComp-KVA / 4-[3,4-bis(fluoranyl)pyrrol-1-yl]-3,5-bis(iodanyl)-2-oxidanyl-benzoic acid


Mass: 490.968 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C11H5F2I2NO3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


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


Mass: 18.015 Da / Num. of mol.: 440 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.48 Å3/Da / Density % sol: 50.48 %
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: 1.47→48.01 Å / Num. obs: 83639 / % possible obs: 99.9 % / Redundancy: 6 % / Biso Wilson estimate: 16.8636649299 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.061 / Net I/σ(I): 15.5
Reflection shellResolution: 1.47→1.5 Å / Redundancy: 6.2 % / Mean I/σ(I) obs: 1.7 / Num. unique obs: 4093 / CC1/2: 0.842 / % possible all: 99.9

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Processing

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

6shz


Resolution: 1.47→48.01 Å / SU ML: 0.150286451132 / Cross valid method: FREE R-VALUE / σ(F): 1.32584953689 / Phase error: 22.4238959466
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.192656164733 4283 5.13302972196 %
Rwork0.163692203263 79157 -
obs0.165252272307 83440 99.6250925329 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 23.2987473696 Å2
Refinement stepCycle: LAST / Resolution: 1.47→48.01 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3041 0 50 440 3531
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.006341466590353274
X-RAY DIFFRACTIONf_angle_d0.8392152478154475
X-RAY DIFFRACTIONf_chiral_restr0.0840278381069489
X-RAY DIFFRACTIONf_plane_restr0.00653590109232629
X-RAY DIFFRACTIONf_dihedral_angle_d17.34001281731245
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.47-1.48670.3018694508271200.2657960697492644X-RAY DIFFRACTION99.6036036036
1.4867-1.50420.2522163381661400.2375451131942606X-RAY DIFFRACTION99.528814788
1.5042-1.52250.2276533395441260.2100524799062591X-RAY DIFFRACTION99.5238095238
1.5225-1.54180.2645779694081280.2054728530392633X-RAY DIFFRACTION99.711087035
1.5418-1.56210.2399914653761370.199216868822596X-RAY DIFFRACTION99.7081357169
1.5621-1.58350.2746879539621180.1884448037322657X-RAY DIFFRACTION99.6767241379
1.5835-1.60610.2256045103861570.181318284652594X-RAY DIFFRACTION99.6739130435
1.6061-1.63010.2403685329981550.1795495020252612X-RAY DIFFRACTION99.8196248196
1.6301-1.65560.2122154556571350.1779303792512609X-RAY DIFFRACTION99.8181156784
1.6556-1.68270.2552569120341490.1872278540962597X-RAY DIFFRACTION99.7457319288
1.6827-1.71170.2391264264891380.1739062898172625X-RAY DIFFRACTION99.7472924188
1.7117-1.74290.2357716629621380.1655508530462620X-RAY DIFFRACTION99.5667870036
1.7429-1.77640.1956800362231380.1493208172692614X-RAY DIFFRACTION99.7101449275
1.7764-1.81270.1917740657911280.1433083055282660X-RAY DIFFRACTION99.785254116
1.8127-1.85210.1642443295881530.141763115782598X-RAY DIFFRACTION99.565689468
1.8521-1.89520.2189191538311540.1484477881752609X-RAY DIFFRACTION99.8554391037
1.8952-1.94260.1865357758241360.1519071592792614X-RAY DIFFRACTION99.6015936255
1.9426-1.99510.1790667547261530.1503313554832631X-RAY DIFFRACTION99.5708154506
1.9951-2.05380.1700479380941400.1550922494692638X-RAY DIFFRACTION99.8562185478
2.0538-2.12010.1977511721381330.1587788987692641X-RAY DIFFRACTION99.7482919813
2.1201-2.19580.175258263681350.1519106016182655X-RAY DIFFRACTION99.6784565916
2.1958-2.28380.1870287613161450.1542008773592626X-RAY DIFFRACTION99.568810636
2.2838-2.38770.1804739413991400.1592489512762665X-RAY DIFFRACTION99.4680851064
2.3877-2.51360.1829938424871460.1633161897152638X-RAY DIFFRACTION99.7134670487
2.5136-2.67110.1918828135861510.1643582341632644X-RAY DIFFRACTION99.785790789
2.6711-2.87730.1789455891331460.1650781429452665X-RAY DIFFRACTION99.7870074547
2.8773-3.16680.1869367953371740.1649206174322648X-RAY DIFFRACTION99.3661971831
3.1668-3.62490.1661440746541460.1575125840812706X-RAY DIFFRACTION99.4768050227
3.6249-4.56640.1743035631091560.1520749740392692X-RAY DIFFRACTION99.0264255911
4.5664-48.010.2163747330981680.1749311437752829X-RAY DIFFRACTION99.2055610725

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