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- PDB-9g6t: p53-Y220C Core Domain Covalently Bound to 5-Chloro-6-methylpyrazi... -

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Basic information

Entry
Database: PDB / ID: 9g6t
Titlep53-Y220C Core Domain Covalently Bound to 5-Chloro-6-methylpyrazine-2-carbonitrile Soaked at 5 mM
ComponentsCellular tumor antigen p53
KeywordsCELL CYCLE / Covalent / SNAr / Stabilization
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
: / DI(HYDROXYETHYL)ETHER / Cellular tumor antigen p53
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.56 Å
AuthorsStahlecker, J. / Klett, T. / Stehle, T. / Boeckler, F.M.
Funding support1items
OrganizationGrant numberCountry
Not funded
Citation
Journal: Drug Des Devel Ther / Year: 2025
Title: SNAr Reactive Pyrazine Derivatives as p53-Y220C Cleft Binders with Diverse Binding Modes
Authors: Klett, T. / Stahlecker, J. / Schwer, M. / Jaag, S.J. / Masberg, B. / Knappe, C. / Lammerhofer, M. / Stehle, T. / Boeckler, F.M.
#1: Journal: Acta Crystallogr.,Sect.D / Year: 2012
Title: Towards automated crystallographic structure refinement with phenix.refine.
Authors: Afonine, P.V. / Grosse-Kunstleve, R.W. / Echols, N. / Headd, J.J. / Moriarty, N.W. / Mustyakimov, M. / Terwilliger, T.C. / Urzhumtsev, A. / Zwart, P.H. / Adams, P.D.
#2: Journal: Acta Crystallogr D Struct Biol / Year: 2019
Title: Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix.
Authors: Dorothee Liebschner / Pavel V Afonine / Matthew L Baker / Gábor Bunkóczi / Vincent B Chen / Tristan I Croll / Bradley Hintze / Li Wei Hung / Swati Jain / Airlie J McCoy / Nigel W Moriarty ...Authors: Dorothee Liebschner / Pavel V Afonine / Matthew L Baker / Gábor Bunkóczi / Vincent B Chen / Tristan I Croll / Bradley Hintze / Li Wei Hung / Swati Jain / Airlie J McCoy / Nigel W Moriarty / Robert D Oeffner / Billy K Poon / Michael G Prisant / Randy J Read / Jane S Richardson / David C Richardson / Massimo D Sammito / Oleg V Sobolev / Duncan H Stockwell / Thomas C Terwilliger / Alexandre G Urzhumtsev / Lizbeth L Videau / Christopher J Williams / Paul D Adams /
Abstract: Diffraction (X-ray, neutron and electron) and electron cryo-microscopy are powerful methods to determine three-dimensional macromolecular structures, which are required to understand biological ...Diffraction (X-ray, neutron and electron) and electron cryo-microscopy are powerful methods to determine three-dimensional macromolecular structures, which are required to understand biological processes and to develop new therapeutics against diseases. The overall structure-solution workflow is similar for these techniques, but nuances exist because the properties of the reduced experimental data are different. Software tools for structure determination should therefore be tailored for each method. Phenix is a comprehensive software package for macromolecular structure determination that handles data from any of these techniques. Tasks performed with Phenix include data-quality assessment, map improvement, model building, the validation/rebuilding/refinement cycle and deposition. Each tool caters to the type of experimental data. The design of Phenix emphasizes the automation of procedures, where possible, to minimize repetitive and time-consuming manual tasks, while default parameters are chosen to encourage best practice. A graphical user interface provides access to many command-line features of Phenix and streamlines the transition between programs, project tracking and re-running of previous tasks.
History
DepositionJul 19, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 11, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)51,64224
Polymers49,0622
Non-polymers2,58122
Water6,882382
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4080 Å2
ΔGint30 kcal/mol
Surface area19130 Å2
Unit cell
Length a, b, c (Å)65.191, 71.145, 105.730
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 / Mutation: Y220C, M133L, V203A, N239Y, N268D
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

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Non-polymers , 7 types, 404 molecules

#2: Chemical
ChemComp-A1II4 / 5-chloranyl-6-methyl-pyrazine-2-carbonitrile


Mass: 153.569 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C6H4ClN3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-EPE / 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID / HEPES


Mass: 238.305 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C8H18N2O4S / Comment: pH buffer*YM
#5: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C4H10O3
#6: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#7: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 382 / 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: 2.5 Å3/Da / Density % sol: 50.75 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.2
Details: 100 mM HEPES (pH = 7.2), 19 % PEG4000 and 10 mM DTT

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.92 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Apr 29, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92 Å / Relative weight: 1
ReflectionResolution: 1.56→50 Å / Num. obs: 70579 / % possible obs: 100 % / Redundancy: 12 % / Biso Wilson estimate: 23.29 Å2 / CC1/2: 0.99 / Rrim(I) all: 0.12 / Net I/σ(I): 13.02
Reflection shellResolution: 1.56→1.66 Å / Redundancy: 12.38 % / Mean I/σ(I) obs: 1.03 / Num. unique obs: 11271 / CC1/2: 0.58 / Rrim(I) all: 2.39

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.56→48.06 Å / SU ML: 0.2194 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 22.3285
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1986 1500 2.13 %
Rwork0.1496 69034 -
obs0.1506 70534 99.91 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 30.49 Å2
Refinement stepCycle: LAST / Resolution: 1.56→48.06 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3009 0 131 382 3522
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00673258
X-RAY DIFFRACTIONf_angle_d0.81094409
X-RAY DIFFRACTIONf_chiral_restr0.0579474
X-RAY DIFFRACTIONf_plane_restr0.012576
X-RAY DIFFRACTIONf_dihedral_angle_d13.14871216
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.56-1.610.39111340.32556173X-RAY DIFFRACTION99.73
1.61-1.670.30871350.25176212X-RAY DIFFRACTION99.97
1.67-1.740.26241340.19546202X-RAY DIFFRACTION100
1.74-1.810.21981360.15626227X-RAY DIFFRACTION99.94
1.81-1.910.18161350.14116219X-RAY DIFFRACTION99.94
1.91-2.030.20181350.13616238X-RAY DIFFRACTION99.84
2.03-2.190.18641360.11916232X-RAY DIFFRACTION99.94
2.19-2.410.17771360.12216277X-RAY DIFFRACTION99.89
2.41-2.750.19591370.14016306X-RAY DIFFRACTION99.94
2.75-3.470.21921380.14786351X-RAY DIFFRACTION99.89
3.47-48.060.17151440.15046597X-RAY DIFFRACTION99.9

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