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- PDB-6rl3: Fragment AZ-003 binding at the p53pT387/14-3-3 sigma interface -

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Basic information

Entry
Database: PDB / ID: 6rl3
TitleFragment AZ-003 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


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 / regulation of epidermal cell division / protein kinase C inhibitor activity / TP53 Regulates Transcription of Caspase Activators and Caspases / negative regulation of mitophagy / cardiac septum morphogenesis / positive regulation of epidermal cell differentiation / keratinocyte development / keratinization / 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) / regulation of cell-cell adhesion / 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 / cAMP/PKA signal transduction / positive regulation of execution phase of apoptosis / Transcriptional Regulation by VENTX / Regulation of localization of FOXO transcription factors / keratinocyte proliferation / replicative senescence / cellular response to UV-C / general transcription initiation factor binding / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / phosphoserine residue binding / 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 / Activation of BAD and translocation to mitochondria / response to X-ray / type II interferon-mediated signaling pathway / hematopoietic stem cell differentiation / negative regulation of keratinocyte proliferation / Pyroptosis / chromosome organization / viral process / establishment of skin barrier / embryonic organ development / negative regulation of protein localization to plasma membrane / somitogenesis / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / glial cell proliferation / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / hematopoietic progenitor cell differentiation / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / core promoter sequence-specific DNA binding / negative regulation of stem cell proliferation
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
5-azanyl-4-phenyl-thiophene-2-carboximidamide / Cellular tumor antigen p53 / 14-3-3 protein sigma
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.3 Å
AuthorsGenet, S. / Wolter, M. / Guillory, X. / Somsen, B. / Leysen, S. / 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
DepositionMay 1, 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 ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_conn_type
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.pdbx_ptnr1_label_alt_id / _struct_conn.pdbx_ptnr2_label_alt_id / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_conn.ptnr2_symmetry / _struct_conn_type.id
Revision 1.3Nov 13, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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)30,0697
Polymers29,6762
Non-polymers3935
Water6,161342
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)60,13914
Polymers59,3524
Non-polymers78710
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_555x,-y,-z1
Buried area6670 Å2
ΔGint-63 kcal/mol
Surface area22700 Å2
MethodPISA
Unit cell
Length a, b, c (Å)81.978, 112.161, 62.702
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221

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Components

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Protein / Protein/peptide , 2 types, 2 molecules AP

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


Mass: 28226.518 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: Residues -4 to 0 are expression tag / 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


Mass: 1449.520 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P04637

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Non-polymers , 5 types, 347 molecules

#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#6: Chemical ChemComp-K48 / 5-azanyl-4-phenyl-thiophene-2-carboximidamide


Mass: 217.290 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H11N3S / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 342 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.62 Å3/Da / Density % sol: 53.1 %
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: SYNCHROTRON / Site: PETRA III, DESY / Beamline: P11 / Wavelength: 0.9999 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Jun 19, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9999 Å / Relative weight: 1
ReflectionResolution: 1.3→62.7 Å / Num. all: 882113 / Num. obs: 71153 / % possible obs: 99.9 % / Redundancy: 12.4 % / CC1/2: 0.999 / Rrim(I) all: 0.085 / Net I/σ(I): 14.9
Reflection shellResolution: 1.3→1.32 Å / Redundancy: 12.3 % / Mean I/σ(I) obs: 2.5 / Num. unique obs: 3463 / CC1/2: 0.99 / Rrim(I) all: 0.802 / % possible all: 98.2

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Processing

Software
NameVersionClassification
PHENIX(1.12_2829: ???)refinement
REFMACrefinement
MOSFLMdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5MOC

5moc


Resolution: 1.3→56.08 Å / SU ML: 0.13 / Cross valid method: FREE R-VALUE / σ(F): 1.47 / Phase error: 18.09
RfactorNum. reflection% reflection
Rfree0.1923 3584 5.04 %
Rwork0.1732 --
obs0.1742 71121 99.88 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.3→56.08 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1888 0 24 342 2254
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0072060
X-RAY DIFFRACTIONf_angle_d1.0012791
X-RAY DIFFRACTIONf_dihedral_angle_d19.742787
X-RAY DIFFRACTIONf_chiral_restr0.179301
X-RAY DIFFRACTIONf_plane_restr0.006370
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.3-1.31710.32461280.28622523X-RAY DIFFRACTION98
1.3171-1.33510.28541420.27072597X-RAY DIFFRACTION100
1.3351-1.35420.24181440.25962545X-RAY DIFFRACTION100
1.3542-1.37440.27911200.25342567X-RAY DIFFRACTION100
1.3744-1.39590.25981410.24342605X-RAY DIFFRACTION100
1.3959-1.41880.24671390.23582561X-RAY DIFFRACTION100
1.4188-1.44330.26851380.23162559X-RAY DIFFRACTION100
1.4433-1.46950.20991440.20242545X-RAY DIFFRACTION100
1.4695-1.49780.22541480.1892592X-RAY DIFFRACTION100
1.4978-1.52830.19771420.18762561X-RAY DIFFRACTION100
1.5283-1.56160.20851250.18282602X-RAY DIFFRACTION100
1.5616-1.59790.20781260.17482568X-RAY DIFFRACTION100
1.5979-1.63790.17071500.16812594X-RAY DIFFRACTION100
1.6379-1.68220.18251300.16482580X-RAY DIFFRACTION100
1.6822-1.73170.17571290.16962614X-RAY DIFFRACTION100
1.7317-1.78760.19331440.16842585X-RAY DIFFRACTION100
1.7876-1.85140.17941400.1812567X-RAY DIFFRACTION100
1.8514-1.92560.20161490.17112597X-RAY DIFFRACTION100
1.9256-2.01320.19121580.16522588X-RAY DIFFRACTION100
2.0132-2.11940.16511270.15582615X-RAY DIFFRACTION100
2.1194-2.25220.15311420.15162620X-RAY DIFFRACTION100
2.2522-2.4260.17721210.1462618X-RAY DIFFRACTION100
2.426-2.67020.17121290.15382661X-RAY DIFFRACTION100
2.6702-3.05650.19541340.16742628X-RAY DIFFRACTION100
3.0565-3.85080.18311520.15822662X-RAY DIFFRACTION100
3.8508-56.13270.19021420.17392783X-RAY DIFFRACTION100

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