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- PDB-6s39: Fragment AZ-018 binding at the p53pT387/14-3-3 sigma interface -

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Basic information

Entry
Database: PDB / ID: 6s39
TitleFragment AZ-018 binding at the p53pT387/14-3-3 sigma interface
Components
  • 14-3-3 protein sigma
  • Cellular tumor antigen p53
KeywordsPEPTIDE BINDING PROTEIN / protein protein interaction / fragment soaking / stabilization
Function / homology
Function and homology information


negative regulation of helicase 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 / negative regulation of pentose-phosphate shunt / ATP-dependent DNA/DNA annealing activity ...negative regulation of helicase 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 / 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 / oligodendrocyte apoptotic process / negative regulation of miRNA processing / intrinsic apoptotic signaling pathway in response to hypoxia / regulation of fibroblast apoptotic process / positive regulation of thymocyte apoptotic process / oxidative stress-induced premature senescence / regulation of tissue remodeling / positive regulation of mitochondrial membrane permeability / mRNA transcription / bone marrow development / positive regulation of programmed necrotic cell death / circadian behavior / T cell proliferation involved in immune response / regulation of mitochondrial membrane permeability involved in apoptotic process / germ cell nucleus / RUNX3 regulates CDKN1A transcription / homolactic fermentation / TP53 Regulates Transcription of Death Receptors and Ligands / Activation of PUMA and translocation to mitochondria / TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain / histone deacetylase regulator activity / regulation of DNA damage response, signal transduction by p53 class mediator / negative regulation of glial cell proliferation / Regulation of TP53 Activity through Association with Co-factors / negative regulation of neuroblast proliferation / mitochondrial DNA repair / T cell lineage commitment / Formation of Senescence-Associated Heterochromatin Foci (SAHF) / ER overload response / thymocyte apoptotic process / B cell lineage commitment / TP53 Regulates Transcription of Caspase Activators and Caspases / entrainment of circadian clock by photoperiod / cardiac septum morphogenesis / regulation of epidermal cell division / protein kinase C inhibitor activity / negative regulation of mitophagy / positive regulation of epidermal cell differentiation / keratinocyte development / keratinization / negative regulation of DNA replication / Zygotic genome activation (ZGA) / positive regulation of release of cytochrome c from mitochondria / PI5P Regulates TP53 Acetylation / Association of TriC/CCT with target proteins during biosynthesis / regulation of cell-cell adhesion / necroptotic process / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / negative regulation of telomere maintenance via telomerase / 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 / rRNA transcription / negative regulation of reactive oxygen species metabolic process / Transcriptional Regulation by VENTX / cAMP/PKA signal transduction / Regulation of localization of FOXO transcription factors / cellular response to UV-C / replicative senescence / keratinocyte proliferation / general transcription initiation factor binding / cellular response to actinomycin D / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / positive regulation of RNA polymerase II transcription preinitiation complex assembly / viral process / neuroblast proliferation / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / positive regulation of execution phase of apoptosis / Pyroptosis / Activation of BAD and translocation to mitochondria / phosphoserine residue binding / hematopoietic stem cell differentiation / embryonic organ development / negative regulation of keratinocyte proliferation / establishment of skin barrier / response to X-ray / chromosome organization / type II interferon-mediated signaling pathway / negative regulation of protein localization to plasma membrane / somitogenesis / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / hematopoietic progenitor cell differentiation / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / glial cell proliferation / negative regulation of fibroblast proliferation / positive regulation of cardiac muscle cell apoptotic process
Similarity search - Function
Cellular tumor antigen p53, transactivation domain 2 / Transactivation domain 2 / p53 transactivation domain / P53 transactivation motif / 14-3-3 domain / p53 family signature. / p53, tetramerisation domain / P53 tetramerisation motif / p53, DNA-binding domain / P53 DNA-binding domain ...Cellular tumor antigen p53, transactivation domain 2 / Transactivation domain 2 / p53 transactivation domain / P53 transactivation motif / 14-3-3 domain / p53 family signature. / p53, tetramerisation domain / P53 tetramerisation motif / p53, DNA-binding domain / P53 DNA-binding domain / p53 tumour suppressor family / Delta-Endotoxin; domain 1 / p53-like tetramerisation domain superfamily / p53/RUNT-type transcription factor, DNA-binding domain superfamily / 14-3-3 protein sigma / 14-3-3 proteins signature 2. / 14-3-3 protein, conserved site / 14-3-3 proteins signature 1. / 14-3-3 protein / 14-3-3 homologues / 14-3-3 domain / 14-3-3 domain superfamily / 14-3-3 protein / p53-like transcription factor, DNA-binding / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-K5Z / Cellular tumor antigen p53 / 14-3-3 protein sigma
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.88 Å
AuthorsGenet, S. / Wolter, M. / Guillory, X. / Somsen, B. / Leysen, S. / Castaldi, P. / Ottmann, C.
Funding support Netherlands, 1items
OrganizationGrant numberCountry
European Commission Netherlands
CitationJournal: J.Med.Chem. / Year: 2020
Title: Fragment-based Differential Targeting of PPI Stabilizer Interfaces.
Authors: Guillory, X. / Wolter, M. / Leysen, S. / Neves, J.F. / Kuusk, A. / Genet, S. / Somsen, B. / Morrow, J.K. / Rivers, E. / van Beek, L. / Patel, J. / Goodnow, R. / Schoenherr, H. / Fuller, N. / ...Authors: Guillory, X. / Wolter, M. / Leysen, S. / Neves, J.F. / Kuusk, A. / Genet, S. / Somsen, B. / Morrow, J.K. / Rivers, E. / van Beek, L. / Patel, J. / Goodnow, R. / Schoenherr, H. / Fuller, N. / Cao, Q. / Doveston, R.G. / Brunsveld, L. / Arkin, M.R. / Castaldi, P. / Boyd, H. / Landrieu, I. / Chen, H. / Ottmann, C.
History
DepositionJun 24, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 17, 2020Provider: repository / Type: Initial release
Revision 1.1Jul 22, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.name
Revision 1.2Jan 24, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / refine / refine_hist
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _refine.pdbx_diffrn_id / _refine_hist.d_res_low
Revision 1.3Nov 13, 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

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Assembly

Deposited unit
A: 14-3-3 protein sigma
P: Cellular tumor antigen p53
hetero molecules


Theoretical massNumber of molelcules
Total (without water)29,9594
Polymers29,6602
Non-polymers2992
Water1,24369
1
A: 14-3-3 protein sigma
P: Cellular tumor antigen p53
hetero molecules

A: 14-3-3 protein sigma
P: Cellular tumor antigen p53
hetero molecules


Theoretical massNumber of molelcules
Total (without water)59,9198
Polymers59,3204
Non-polymers5994
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_555x,-y,-z1
Buried area5370 Å2
ΔGint-49 kcal/mol
Surface area22520 Å2
MethodPISA
Unit cell
Length a, b, c (Å)82.110, 111.990, 62.520
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221

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Components

#1: Protein 14-3-3 protein sigma / Epithelial cell marker protein 1 / Stratifin


Mass: 28210.518 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SFN, HME1 / Production host: Escherichia coli (E. coli) / References: UniProt: P31947
#2: Protein/peptide Cellular tumor antigen p53 / Antigen NY-CO-13 / Phosphoprotein p53 / Tumor suppressor p53 / p53pT387


Mass: 1449.520 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P04637
#3: Chemical ChemComp-K5Z / 5-(3-azanylpropyl)-4-phenyl-thiophene-2-carboximidamide


Mass: 259.370 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H17N3S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ca
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 69 / Source method: isolated from a natural source / Formula: H2O
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: 2.42 Å3/Da / Density % sol: 49.23 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 0.1M Hepes, pH7.5, 27%PEG, 5% Glycerol, 0.2M Calcium Chloride, 2mM DTT.

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SEALED TUBE / Type: RIGAKU MICROMAX-003 / Wavelength: 1.54187 Å
DetectorType: DECTRIS PILATUS 200K / Detector: PIXEL / Date: Jul 25, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54187 Å / Relative weight: 1
ReflectionResolution: 1.88→26.59 Å / Num. obs: 23688 / % possible obs: 100 % / Redundancy: 5.7 % / CC1/2: 0.937 / Rmerge(I) obs: 0.266 / Rrim(I) all: 0.322 / Net I/σ(I): 3.7
Reflection shellResolution: 1.88→1.93 Å / Redundancy: 5.4 % / Rmerge(I) obs: 0.412 / Mean I/σ(I) obs: 4 / Num. unique obs: 1495 / CC1/2: 0.809 / Rrim(I) all: 0.5 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.8.0238refinement
MOSFLMdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5MOC

5moc


Resolution: 1.88→26.59 Å / Cor.coef. Fo:Fc: 0.681 / Cor.coef. Fo:Fc free: 0.668 / SU B: 6.193 / SU ML: 0.172 / Cross valid method: THROUGHOUT / ESU R: 0.259 / ESU R Free: 0.226 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.38783 1161 4.9 %RANDOM
Rwork0.35395 ---
obs0.35558 22475 99.7 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 8.46 Å2
Baniso -1Baniso -2Baniso -3
1-0.3 Å20 Å2-0 Å2
2---0.02 Å20 Å2
3----0.28 Å2
Refinement stepCycle: LAST / Resolution: 1.88→26.59 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1877 0 19 69 1965
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0132032
X-RAY DIFFRACTIONr_bond_other_d0.0010.0171894
X-RAY DIFFRACTIONr_angle_refined_deg1.4051.6722755
X-RAY DIFFRACTIONr_angle_other_deg1.3131.6024418
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.555264
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.52323.241108
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.00615380
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.8791513
X-RAY DIFFRACTIONr_chiral_restr0.0720.2263
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.022294
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02417
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.6150.864988
X-RAY DIFFRACTIONr_mcbond_other0.6080.862987
X-RAY DIFFRACTIONr_mcangle_it1.051.2791238
X-RAY DIFFRACTIONr_mcangle_other1.0511.2821239
X-RAY DIFFRACTIONr_scbond_it0.6140.9441044
X-RAY DIFFRACTIONr_scbond_other0.6130.9461045
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other1.0321.3971503
X-RAY DIFFRACTIONr_long_range_B_refined2.4559.7872315
X-RAY DIFFRACTIONr_long_range_B_other2.3989.7382304
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.884→1.933 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.587 89 -
Rwork0.628 1631 -
obs--99.54 %

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