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- PDB-6rwu: Fragment AZ-010 binding at the p53pT387/14-3-3 sigma interface -

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Basic information

Entry
Database: PDB / ID: 6rwu
TitleFragment AZ-010 binding at the p53pT387/14-3-3 sigma interface
Components
  • 14-3-3 protein sigma
  • Cellular tumor antigen p53P53
KeywordsPEPTIDE BINDING PROTEIN / protein protein interaction / fragment soaking / stabilization
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 / glucose catabolic process to lactate via pyruvate / regulation of tissue remodeling / positive regulation of mitochondrial membrane permeability / negative regulation of mitophagy / positive regulation of programmed necrotic cell death / mRNA transcription / bone marrow development / circadian behavior / T cell proliferation involved in immune response / regulation of mitochondrial membrane permeability involved in apoptotic process / histone deacetylase regulator activity / RUNX3 regulates CDKN1A transcription / germ cell nucleus / 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 / negative regulation of neuroblast proliferation / negative regulation of glial cell proliferation / Formation of Senescence-Associated Heterochromatin Foci (SAHF) / Regulation of TP53 Activity through Association with Co-factors / positive regulation of execution phase of apoptosis / mitochondrial DNA repair / T cell lineage commitment / negative regulation of DNA replication / ER overload response / regulation of epidermal cell division / protein kinase C inhibitor activity / B cell lineage commitment / thymocyte apoptotic process / positive regulation of epidermal cell differentiation / 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 / keratinocyte development / keratinization / TP53 Regulates Transcription of Caspase Activators and Caspases / cardiac septum morphogenesis / entrainment of circadian clock by photoperiod / PI5P Regulates TP53 Acetylation / Association of TriC/CCT with target proteins during biosynthesis / Zygotic genome activation (ZGA) / necroptotic process / rRNA transcription / positive regulation of release of cytochrome c from mitochondria / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / TFIID-class transcription factor complex binding / mitophagy / negative regulation of telomere maintenance via telomerase / SUMOylation of transcription factors / Regulation of localization of FOXO transcription factors / intrinsic apoptotic signaling pathway by p53 class mediator / general transcription initiation factor binding / neuroblast proliferation / keratinocyte proliferation / cellular response to actinomycin D / Transcriptional Regulation by VENTX / response to X-ray / DNA damage response, signal transduction by p53 class mediator / replicative senescence / chromosome organization / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / phosphoserine residue binding / gastrulation / cellular response to UV-C / response to inorganic substance / Activation of BAD and translocation to mitochondria / hematopoietic stem cell differentiation / positive regulation of RNA polymerase II transcription preinitiation complex assembly / negative regulation of reactive oxygen species metabolic process / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / negative regulation of keratinocyte proliferation / MDM2/MDM4 family protein binding / embryonic organ development / establishment of skin barrier / glial cell proliferation / Pyroptosis / cis-regulatory region sequence-specific DNA binding / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / hematopoietic progenitor cell differentiation / cellular response to glucose starvation / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest
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 / 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
Similarity search - Domain/homology
Chem-KM8 / Cellular tumor antigen p53 / 14-3-3 protein sigma
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.46 Å
AuthorsLeysen, S. / Guillory, X. / Wolter, M. / Genet, S. / Somsen, B. / Patel, J. / 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 6, 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
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)29,9333
Polymers29,6602
Non-polymers2731
Water6,485360
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)59,8676
Polymers59,3204
Non-polymers5472
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_555x,-y,-z1
Buried area5160 Å2
ΔGint-24 kcal/mol
Surface area22940 Å2
MethodPISA
Unit cell
Length a, b, c (Å)82.117, 111.852, 62.884
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11A-403-

HOH

21A-732-

HOH

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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 / P53 / Antigen NY-CO-13 / Phosphoprotein p53 / Tumor suppressor p53


Mass: 1449.520 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P04637
#3: Chemical ChemComp-KM8 / ~{N}-[3-(5-carbamimidoylthiophen-3-yl)phenyl]propanamide


Mass: 273.353 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H15N3OS / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 360 / Source method: isolated from a natural source / Formula: H2O

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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: 2.47 Å3/Da / Density % sol: 50.2 %
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: ROTATING ANODE / Type: RIGAKU FR-E+ SUPERBRIGHT / Wavelength: 1.54 Å
DetectorType: RIGAKU SATURN 944+ / Detector: CCD / Date: Jun 28, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 1.46→66.19 Å / Num. obs: 40944 / % possible obs: 80.3 % / Redundancy: 6.3 % / Biso Wilson estimate: 7.49 Å2 / CC1/2: 0.997 / Net I/σ(I): 19
Reflection shellResolution: 1.46→1.53 Å / Redundancy: 2.7 % / Mean I/σ(I) obs: 3.3 / Num. unique obs: 1436 / CC1/2: 0.777 / % possible all: 19.8

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Processing

Software
NameVersionClassification
BUSTER2.11.7 PACIOREKrefinement
MOSFLMdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5MOC

5moc


Resolution: 1.46→21.38 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.922 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.083 / Cross valid method: FREE R-VALUE / σ(F): 0 / SU R Blow DPI: 0.093 / SU Rfree Blow DPI: 0.091 / SU Rfree Cruickshank DPI: 0.085
RfactorNum. reflection% reflectionSelection details
Rfree0.221 2050 5.01 %RANDOM
Rwork0.19 ---
obs0.191 40880 80.9 %-
Displacement parametersBiso mean: 18.97 Å2
Baniso -1Baniso -2Baniso -3
1--1.7072 Å20 Å20 Å2
2--1.6376 Å20 Å2
3---0.0696 Å2
Refine analyzeLuzzati coordinate error obs: 0.21 Å
Refinement stepCycle: LAST / Resolution: 1.46→21.38 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1889 0 30 367 2286
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012158HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.982956HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d854SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes65HARMONIC2
X-RAY DIFFRACTIONt_gen_planes338HARMONIC5
X-RAY DIFFRACTIONt_it2158HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.77
X-RAY DIFFRACTIONt_other_torsion16.23
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion288SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2967SEMIHARMONIC4
LS refinement shellResolution: 1.46→1.5 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.723 -3.82 %
Rwork0.587 403 -
all0.594 419 -
obs--11.32 %

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