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- PDB-9br3: Crystal structure of p53 Y220C mutant in complex with PC-10709 -

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Basic information

Entry
Database: PDB / ID: 9br3
TitleCrystal structure of p53 Y220C mutant in complex with PC-10709
ComponentsCellular tumor antigen p53
KeywordsTRANSFERASE / P53 / Y220C mutant / ligand
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 / bone marrow development / circadian behavior / regulation of mitochondrial membrane permeability involved in apoptotic process / germ cell nucleus / 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 / regulation of DNA damage response, signal transduction by p53 class mediator / 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 / cardiac septum morphogenesis / negative regulation of DNA replication / entrainment of circadian clock by photoperiod / PI5P Regulates TP53 Acetylation / negative regulation of telomere maintenance via telomerase / Zygotic genome activation (ZGA) / positive regulation of release of cytochrome c from mitochondria / Association of TriC/CCT with target proteins during biosynthesis / necroptotic process / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / TFIID-class transcription factor complex binding / 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 / T cell proliferation involved in immune response / negative regulation of reactive oxygen species metabolic process / positive regulation of execution phase of apoptosis / Transcriptional Regulation by VENTX / general transcription initiation factor binding / replicative senescence / cellular response to UV-C / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / positive regulation of RNA polymerase II transcription preinitiation complex assembly / cellular response to actinomycin D / neuroblast proliferation / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / hematopoietic stem cell differentiation / response to X-ray / type II interferon-mediated signaling pathway / Pyroptosis / viral process / chromosome organization / embryonic organ development / somitogenesis / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / glial cell proliferation / hematopoietic progenitor cell differentiation / core promoter sequence-specific DNA binding / negative regulation of stem cell proliferation / cis-regulatory region sequence-specific DNA binding / cellular response to glucose starvation / mitophagy / positive regulation of peptidyl-tyrosine phosphorylation / negative regulation of fibroblast proliferation / positive regulation of cardiac muscle cell apoptotic process / positive regulation of intrinsic apoptotic signaling pathway / tumor necrosis factor-mediated signaling pathway / Regulation of TP53 Activity through Acetylation / mitotic G1 DNA damage checkpoint signaling / gastrulation / 14-3-3 protein binding / response to salt stress / MDM2/MDM4 family 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
: / Cellular tumor antigen p53
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.9 Å
AuthorsAbendroth, J. / Lorimer, D.D. / Vu, B. / Tanaka, N.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: Cancer Discov / Year: 2025
Title: Restoration of the Tumor Suppressor Function of Y220C-Mutant p53 by Rezatapopt, a Small Molecule Reactivator.
Authors: Puzio-Kuter, A.M. / Xu, L. / McBrayer, M.K. / Dominique, R. / Li, H.H. / Fahr, B.J. / Brown, A.M. / Wiebesiek, A.E. / Russo, B.M. / Mulligan, C.L. / Yang, H. / Battaglia, J. / Robell, K.A. / ...Authors: Puzio-Kuter, A.M. / Xu, L. / McBrayer, M.K. / Dominique, R. / Li, H.H. / Fahr, B.J. / Brown, A.M. / Wiebesiek, A.E. / Russo, B.M. / Mulligan, C.L. / Yang, H. / Battaglia, J. / Robell, K.A. / Thomas, D.H. / Huang, K.S. / Solovyov, A. / Greenbaum, B.D. / Oliner, J.D. / Davis, T.W. / Dumble, M.L. / Johnson, M.L. / Xiong, S. / Yang, P. / Lozano, G. / Fellous, M.M. / Vu, B.T. / Schram, A.M. / Levine, A.J. / Poyurovsky, M.V.
History
DepositionMay 10, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 26, 2025Provider: repository / Type: Initial release

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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)50,5786
Polymers49,3502
Non-polymers1,2284
Water9,476526
1
A: Cellular tumor antigen p53
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,2893
Polymers24,6751
Non-polymers6142
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Cellular tumor antigen p53
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,2893
Polymers24,6751
Non-polymers6142
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)64.960, 71.210, 104.850
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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: 24674.943 Da / Num. of mol.: 2 / Mutation: Y220C
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TP53, P53 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P04637
#2: Chemical ChemComp-A1ARO / 2-{3-[4-(methanesulfonyl)-2-methoxyanilino]prop-1-yn-1-yl}-N-(1-methylpiperidin-4-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-4-amine


Mass: 548.620 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H31F3N4O3S / 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: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 526 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 2.46 Å3/Da / Density % sol: 49.99 %
Crystal growTemperature: 289 K / Method: vapor diffusion, sitting drop
Details: p53, CID 3799, at 6.93mg/ml; Optimization screen PMV1-opt1 e3: 16% PEG 8000, 20% glycerol, 20mM K2HPO4; protein + 1mM BSI 107743; cryo: direct; crystal tracking ID 285723e3, puck tai0-7

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.97872 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Nov 9, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97872 Å / Relative weight: 1
ReflectionResolution: 1.9→47.991 Å / Num. obs: 38106 / % possible obs: 97.6 % / Redundancy: 6.097 % / Biso Wilson estimate: 13.594 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.098 / Rrim(I) all: 0.107 / Χ2: 0.938 / Net I/σ(I): 14.91 / Num. measured all: 232344
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsCC1/2Rrim(I) all% possible all
1.9-1.955.340.394.1712266283122970.9330.43281.1
1.95-25.6180.3375.0815286278227210.9330.37297.8
2-2.066.2480.3066.0916594270326560.9580.33498.3
2.06-2.126.2860.2677.0716162261325710.9690.29198.4
2.12-2.196.290.2178.4615926256825320.9820.23698.6
2.19-2.276.270.1929.5315105244624090.9830.20998.5
2.27-2.366.2740.16510.7214870239823700.9880.1898.8
2.36-2.456.2720.15311.314188230022620.990.16798.3
2.45-2.566.270.13512.5313613219421710.9910.14799
2.56-2.696.250.12113.8513224213221160.9930.13199.2
2.69-2.836.2230.10316.1312464201920030.9940.11299.2
2.83-36.2420.08618.2111754190118830.9970.09499.1
3-3.216.1880.06722.4211089179817920.9980.07499.7
3.21-3.476.1540.05625.9610278168116700.9980.06299.3
3.47-3.86.1110.04928.939466155815490.9980.05499.4
3.8-4.256.0760.04132.218580142014120.9990.04599.4
4.25-4.916.0250.03933.737591126412600.9990.04399.7
4.91-6.015.9340.03931.816403108210790.9990.04399.7
6.01-8.55.7460.04329.2848848518500.9990.04799.9
8.5-47.9915.1710.03432.8626015115030.9980.03898.4

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
PHENIX1.11.1_2575refinement
PDB_EXTRACT3.28data extraction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.9→47.991 Å / SU ML: 0.16 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 18.02 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.191 2036 5.34 %0
Rwork0.1516 36059 --
obs0.1537 38095 97.55 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 73.67 Å2 / Biso mean: 17.8918 Å2 / Biso min: 5.29 Å2
Refinement stepCycle: final / Resolution: 1.9→47.991 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3041 0 78 531 3650
Biso mean--18.04 27.58 -
Num. residues----398
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0073290
X-RAY DIFFRACTIONf_angle_d0.8294514
X-RAY DIFFRACTIONf_chiral_restr0.056494
X-RAY DIFFRACTIONf_plane_restr0.007587
X-RAY DIFFRACTIONf_dihedral_angle_d14.9852018
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.9-1.94410.24521140.1873193280
1.9441-1.99280.20831290.176234297
1.9928-2.04660.22691320.1657238098
2.0466-2.10690.22141420.1625239898
2.1069-2.17490.18891550.1488237699
2.1749-2.25260.18471370.1422238599
2.2526-2.34280.19851330.1458241799
2.3428-2.44940.20191190.1476243599
2.4494-2.57850.20151480.1543241599
2.5785-2.74010.19291320.1548245999
2.7401-2.95160.19331540.1536242899
2.9516-3.24860.18441350.1485246999
3.2486-3.71850.16031280.14142474100
3.7185-4.68430.15881290.1331251499
4.6843-47.990.20081490.16522635100
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
13.43760.6653-0.72654.8994-1.45094.10190.18630.24440.1848-0.0775-0.2185-0.1357-0.21580.35710.07070.10490.0325-0.0310.1285-0.00030.1159140.0819-61.512538.5907
20.52620.2033-0.06131.72770.03680.5762-0.03450.1036-0.0065-0.12380.07470.02070.05910.0153-0.02950.06-0.0023-0.01440.0966-0.00760.0797130.4643-58.636428.6801
30.6801-0.05740.06421.952-0.14860.9382-0.01380.09130.0769-0.17220.01650.05670.03770.0405-0.0030.0562-0.0145-0.00610.09840.00190.088128.9466-53.09329.7676
41.99951.5932-0.76043.0363-0.37441.3245-0.1292-0.06730.1376-0.0854-0.0732-0.1753-0.06350.21960.17460.0907-0.0057-0.05870.12190.01730.1107171.3886-52.905737.4195
50.1845-0.1733-0.11431.4317-0.24352.21380.06530.0188-0.0315-0.1483-0.02680.09550.1442-0.0703-0.06270.072-0.008-0.01090.0884-0.0030.0937158.554-55.085727.846
60.3531-0.24910.37652.403-1.16231.30430.05850.03480.0712-0.1316-0.0935-0.18890.05810.08570.0410.0808-0.0224-0.01980.0918-0.00530.1012168.5728-39.256927.7693
71.78430.0235-0.37572.93710.13522.94390.0581-0.06310.16770.2092-0.01440.0903-0.3269-0.0631-0.03990.1151-0.01390.00010.0754-0.01280.1309159.9245-36.896934.4833
83.90283.93810.13465.87390.55660.09860.0224-0.0861-0.08810.0047-0.14690.1320.1598-0.33930.06460.1281-0.0608-0.01040.1944-0.01520.0992155.0589-53.390340.7892
93.03270.9716-0.67384.1657-1.44792.08920.04590.08580.1028-0.1871-0.06770.0253-0.06540.02080.01590.08440.002-0.03230.0762-0.01190.068161.9725-43.061424.0316
100.9322-0.43370.1881.2941-0.75352.75470.03010.04380.048-0.0042-0.0189-0.0166-0.01840.23390.03310.0517-0.0303-0.00660.0778-0.0040.0857166.37-49.735932.9739
112.43760.5222-1.59972.32720.29412.2010.02090.5171-0.2954-0.5966-0.2589-0.26580.3910.5870.12230.30930.10040.04070.3032-0.00830.1162165.4654-57.119512.2212
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 95 through 109 )A95 - 109
2X-RAY DIFFRACTION2chain 'A' and (resid 110 through 176 )A110 - 176
3X-RAY DIFFRACTION3chain 'A' and (resid 177 through 291 )A177 - 291
4X-RAY DIFFRACTION4chain 'B' and (resid 92 through 112 )B92 - 112
5X-RAY DIFFRACTION5chain 'B' and (resid 113 through 155 )B113 - 155
6X-RAY DIFFRACTION6chain 'B' and (resid 156 through 181 )B156 - 181
7X-RAY DIFFRACTION7chain 'B' and (resid 182 through 213 )B182 - 213
8X-RAY DIFFRACTION8chain 'B' and (resid 214 through 229 )B214 - 229
9X-RAY DIFFRACTION9chain 'B' and (resid 230 through 250 )B230 - 250
10X-RAY DIFFRACTION10chain 'B' and (resid 251 through 277 )B251 - 277
11X-RAY DIFFRACTION11chain 'B' and (resid 278 through 292 )B278 - 292

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