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- PDB-8dc8: Crystal structure of p53 Y220C covalently bound to azaindole KG13 -

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Basic information

Entry
Database: PDB / ID: 8dc8
TitleCrystal structure of p53 Y220C covalently bound to azaindole KG13
ComponentsCellular tumor antigen p53
KeywordsCELL CYCLE / 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 / 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-R50 / Cellular tumor antigen p53
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.72009735908 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Cellular tumor antigen p53
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,3836
Polymers24,7541
Non-polymers6295
Water3,531196
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)68.279, 85.950, 84.140
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221
Space group name HallC2c2
Symmetry operation#1: x,y,z
#2: x,-y,-z
#3: -x,y,-z+1/2
#4: -x,-y,z+1/2
#5: x+1/2,y+1/2,z
#6: x+1/2,-y+1/2,-z
#7: -x+1/2,y+1/2,-z+1/2
#8: -x+1/2,-y+1/2,z+1/2
Components on special symmetry positions
IDModelComponents
11A-574-

HOH

21A-646-

HOH

31A-687-

HOH

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Components

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Protein , 1 types, 1 molecules A

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


Mass: 24753.869 Da / Num. of mol.: 1
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, 201 molecules

#2: Chemical ChemComp-R50 / 2-methyl-1-[(4P)-3-methyl-4-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl]prop-2-en-1-one, bound form


Mass: 347.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H25N3O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 196 / 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: 2.49 Å3/Da / Density % sol: 50.67 %
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: 1.72009735908→53.46 Å / Num. obs: 26016 / % possible obs: 97.9 % / Redundancy: 13.7 % / Biso Wilson estimate: 16.3820548616 Å2 / CC1/2: 0.999 / Net I/σ(I): 19.6
Reflection shellResolution: 1.72009735908→1.72009735908 Å / Num. unique obs: 1280 / CC1/2: 0.895

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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: 1.72009735908→33.0612965 Å / SU ML: 0.164187042494 / Cross valid method: FREE R-VALUE / σ(F): 1.37999454432 / Phase error: 17.5140133485
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.204132714926 1279 4.92188101285 %
Rwork0.169763302239 24707 -
obs0.17140833784 25986 97.5816748029 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 21.5916198793 Å2
Refinement stepCycle: LAST / Resolution: 1.72009735908→33.0612965 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1551 0 38 196 1785
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00645575917971633
X-RAY DIFFRACTIONf_angle_d0.9579729999962223
X-RAY DIFFRACTIONf_chiral_restr0.0563840338381239
X-RAY DIFFRACTIONf_plane_restr0.00510862099395288
X-RAY DIFFRACTIONf_dihedral_angle_d12.2786611548986
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.7201-1.7890.251059171431350.2270627549642609X-RAY DIFFRACTION94.4903581267
1.789-1.87040.2271110969341260.181791827092692X-RAY DIFFRACTION96.6061021598
1.8704-1.9690.2002797559861410.1628821302612710X-RAY DIFFRACTION97.3037542662
1.969-2.09230.1944393885211570.1641092362572683X-RAY DIFFRACTION97.3603016798
2.0923-2.25380.216278615541480.1650613642992725X-RAY DIFFRACTION97.7210884354
2.2538-2.48060.2218157628081400.1740750790492760X-RAY DIFFRACTION98.1719702099
2.4806-2.83940.208412881751380.1773746364832781X-RAY DIFFRACTION98.31593129
2.8394-3.57660.1923047532791480.1649294415982814X-RAY DIFFRACTION98.9973262032

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