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- PDB-8dc6: Crystal structure of p53 Y220C covalently bound to indole KG6 -

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Basic information

Entry
Database: PDB / ID: 8dc6
TitleCrystal structure of p53 Y220C covalently bound to indole KG6
ComponentsCellular tumor antigen p53
KeywordsCELL CYCLE / p53 / TP53 / tumor suppressor
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 / 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 / negative regulation of mitophagy / 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 / rRNA transcription / TFIID-class transcription factor complex binding / 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 / replicative senescence / cellular response to UV-C / general transcription initiation factor binding / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / cellular response to actinomycin D / neuroblast proliferation / positive regulation of RNA polymerase II transcription preinitiation complex assembly / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / response to X-ray / type II interferon-mediated signaling pathway / hematopoietic stem cell differentiation / Pyroptosis / chromosome organization / viral process / 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 / cellular response to glucose starvation / cis-regulatory region sequence-specific DNA binding / mitophagy / 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 / negative regulation of proteolysis / 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 / cardiac muscle cell apoptotic process / transcription repressor complex
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-R4F / Cellular tumor antigen p53
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.60000908706 Å
AuthorsGuiley, K.Z. / Shokat, K.M.
Funding support United States, 1items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI)DRG: 2399-20 United States
CitationJournal: Cancer Discov / Year: 2023
Title: A Small Molecule Reacts with the p53 Somatic Mutant Y220C to Rescue Wild-type Thermal Stability.
Authors: Guiley, K.Z. / Shokat, K.M.
History
DepositionJun 15, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 12, 2022Provider: repository / Type: Initial release
Revision 1.1Jan 18, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation.year
Revision 1.2Oct 25, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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
C: Cellular tumor antigen p53
D: Cellular tumor antigen p53
hetero molecules


Theoretical massNumber of molelcules
Total (without water)101,92427
Polymers99,5044
Non-polymers2,42023
Water11,205622
1
A: Cellular tumor antigen p53
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,6378
Polymers24,8761
Non-polymers7617
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Cellular tumor antigen p53
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,4697
Polymers24,8761
Non-polymers5936
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Cellular tumor antigen p53
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,3736
Polymers24,8761
Non-polymers4975
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Cellular tumor antigen p53
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,4456
Polymers24,8761
Non-polymers5695
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)91.040, 105.750, 105.750
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, 4 molecules ABCD

#1: Protein
Cellular tumor antigen p53 / Antigen NY-CO-13 / Phosphoprotein p53 / Tumor suppressor p53


Mass: 24876.016 Da / Num. of mol.: 4 / Mutation: Y220C
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, 645 molecules

#2: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 13 / Source method: obtained synthetically / Formula: SO4
#4: Chemical
ChemComp-R4F / 1-(2-methylprop-2-enoyl)-1H-indole-3-carbaldehyde, bound form


Mass: 215.248 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C13H13NO2 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 622 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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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: 2.56 Å3/Da / Density % sol: 51.91 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7 / Details: 100 mM HEPES, 2.2M MgSO4

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Data collection

DiffractionMean temperature: 80 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.2.1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Dec 16, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.6→57.78 Å / Num. obs: 133925 / % possible obs: 99 % / Redundancy: 2 % / Biso Wilson estimate: 15.2051228967 Å2 / CC1/2: 0.999 / Net I/σ(I): 20.3
Reflection shellResolution: 1.6→1.6 Å / Num. unique obs: 13159 / CC1/2: 0.947

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Processing

Software
NameVersionClassification
Blu-Icedata collection
iMOSFLMdata reduction
Aimlessdata scaling
PHASERphasing
PHENIX1.20.1refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2J1X

2j1x


Resolution: 1.60000908706→47.2928377241 Å / SU ML: 0.166831907581 / Cross valid method: FREE R-VALUE / σ(F): 1.34297848669 / Phase error: 18.9413581216
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.202329214824 6607 4.9344635722 %
Rwork0.181395773567 127288 -
obs0.182425826238 133895 99.3721287507 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 21.5712440779 Å2
Refinement stepCycle: LAST / Resolution: 1.60000908706→47.2928377241 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6053 0 135 622 6810
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.008128426738046401
X-RAY DIFFRACTIONf_angle_d1.263361124168727
X-RAY DIFFRACTIONf_chiral_restr0.0631557693318938
X-RAY DIFFRACTIONf_plane_restr0.008359594299151135
X-RAY DIFFRACTIONf_dihedral_angle_d15.20336727513893
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.60000908706-1.61820.2593434833872030.2294096579964140X-RAY DIFFRACTION98.4583994559
1.6182-1.63720.2396939964881970.2219332331334172X-RAY DIFFRACTION98.6230248307
1.6372-1.65720.2310893119322360.2046669169844211X-RAY DIFFRACTION98.5812458435
1.6572-1.67820.2116046051681810.194568896884156X-RAY DIFFRACTION98.5457850489
1.6782-1.70030.2360738199232270.1929832624284217X-RAY DIFFRACTION98.9755011136
1.7003-1.72360.2305804207082370.1922238463094140X-RAY DIFFRACTION98.9376130199
1.7236-1.74820.208073631942310.192657457494140X-RAY DIFFRACTION99.0707162285
1.7482-1.77430.2152791601242460.1883718855734165X-RAY DIFFRACTION98.9457155675
1.7743-1.8020.1936798361442150.1766686712574185X-RAY DIFFRACTION98.9431077131
1.802-1.83150.1897525996362000.1727455536414252X-RAY DIFFRACTION98.9993328886
1.8315-1.86310.2028088291312320.1751949665974202X-RAY DIFFRACTION99.1502683363
1.8631-1.8970.1910395782862460.1802761449884153X-RAY DIFFRACTION99.2106450158
1.897-1.93350.2250785455732000.1908662411934213X-RAY DIFFRACTION99.3471409275
1.9335-1.9730.2102461191242630.186694732554173X-RAY DIFFRACTION99.4173016584
1.973-2.01590.2118490355462120.1729832201594215X-RAY DIFFRACTION99.4607953269
2.0159-2.06280.2066340575982150.1831909251484265X-RAY DIFFRACTION99.6662958843
2.0628-2.11430.1905399277822000.1837640422274265X-RAY DIFFRACTION99.3104982206
2.1143-2.17150.2127762517072330.1789277408384205X-RAY DIFFRACTION99.6631484393
2.1715-2.23540.2092736935112080.1779591091494243X-RAY DIFFRACTION99.7311225633
2.2354-2.30760.1848225343092360.1753876081224238X-RAY DIFFRACTION99.5771199644
2.3076-2.390.2018160487231940.1868809563254302X-RAY DIFFRACTION99.9111111111
2.39-2.48570.199929566161910.1842849568254293X-RAY DIFFRACTION99.7774810859
2.4857-2.59880.2233420196922480.1868760216384238X-RAY DIFFRACTION99.8664292075
2.5988-2.73580.2063689303062330.1927999745224285X-RAY DIFFRACTION99.8894539023
2.7358-2.90720.2235025532031990.1941619058134305X-RAY DIFFRACTION99.9556147359
2.9072-3.13160.227211481572180.1885397556434296X-RAY DIFFRACTION99.9778516058
3.1316-3.44670.1899848026242390.1687232544284301X-RAY DIFFRACTION100
3.4467-3.94520.1919829459972120.1583797318214383X-RAY DIFFRACTION99.9782419495
3.9452-4.96970.1663735917112220.1597034193344397X-RAY DIFFRACTION99.9783549784

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