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- PDB-6slv: Fragment AZ-013 binding at the p53pT387/14-3-3 sigma interface -

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Basic information

Entry
Database: PDB / ID: 6slv
TitleFragment AZ-013 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 / regulation of fibroblast apoptotic process / oligodendrocyte apoptotic process / negative regulation of miRNA processing / intrinsic apoptotic signaling pathway in response to hypoxia / 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 / glucose catabolic process to lactate via pyruvate / 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 / 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 / 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 / cardiac septum morphogenesis / negative regulation of mitophagy / regulation of epidermal cell division / protein kinase C inhibitor activity / negative regulation of DNA replication / entrainment of circadian clock by photoperiod / positive regulation of epidermal cell differentiation / keratinocyte development / keratinization / negative regulation of telomere maintenance via telomerase / 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 / 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 / negative regulation of reactive oxygen species metabolic process / rRNA transcription / Transcriptional Regulation by VENTX / cAMP/PKA signal transduction / Regulation of localization of FOXO transcription factors / cellular response to UV-C / replicative senescence / general transcription initiation factor binding / keratinocyte proliferation / 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 / positive regulation of execution phase of apoptosis / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / neuroblast proliferation / Pyroptosis / phosphoserine residue binding / Activation of BAD and translocation to mitochondria / viral process / hematopoietic stem cell differentiation / response to X-ray / negative regulation of keratinocyte proliferation / embryonic organ development / establishment of skin barrier / 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 / glial cell proliferation / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / 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-LJW / Cellular tumor antigen p53 / 14-3-3 protein sigma
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsOttmann, C. / Wolter, M. / Guillory, X. / Leysen, S. / Genet, S. / Somsen, B. / Patel, J. / Castaldi, P.
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
DepositionAug 20, 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_alt_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.ptnr1_symmetry / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr2_symmetry / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_alt_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.ptnr3_symmetry / _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.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 6, 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

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)28,3647
Polymers27,9922
Non-polymers3725
Water5,026279
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)56,72814
Polymers55,9854
Non-polymers74310
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_555x,-y,-z1
Buried area5830 Å2
ΔGint-70 kcal/mol
Surface area23620 Å2
MethodPISA
Unit cell
Length a, b, c (Å)82.322, 112.398, 62.672
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-303-

MG

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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: 26542.914 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


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 , 4 types, 284 molecules

#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 3 / 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-LJW / 4-(methylamino)-7-propan-2-yloxy-1-benzothiophene-2-carboximidamide


Mass: 263.359 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H17N3OS / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 279 / 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: 2.59 Å3/Da / Density % sol: 52.5 %
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: Oct 14, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54187 Å / Relative weight: 1
ReflectionResolution: 1.9→41.84 Å / Num. obs: 23310 / % possible obs: 99.97 % / Redundancy: 2 % / Biso Wilson estimate: 11.2288685469 Å2 / CC1/2: 0.996 / Rmerge(I) obs: 0.05203 / Rrim(I) all: 0.07358 / Net I/σ(I): 10.31
Reflection shellResolution: 1.9→1.968 Å / Rmerge(I) obs: 0.1837 / Mean I/σ(I) obs: 2.98 / Num. unique obs: 2300 / CC1/2: 0.916 / Rrim(I) all: 0.2598 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMACrefinement
PHENIX1.12_2829refinement
DIALSdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5MOC

5moc


Resolution: 1.9→41.84 Å / Cross valid method: FREE R-VALUE
RfactorNum. reflection% reflection
Rfree0.2184 --
Rwork0.1877 --
obs-23308 99.88 %
Refinement stepCycle: LAST / Resolution: 1.9→41.84 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1920 0 22 279 2221
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01055034866682029
X-RAY DIFFRACTIONf_angle_d1.009683943752745
X-RAY DIFFRACTIONf_chiral_restr0.046838674175298
X-RAY DIFFRACTIONf_plane_restr0.00605270094426361
X-RAY DIFFRACTIONf_dihedral_angle_d13.85024673391247
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9-1.94130.3097646542481370.2518076810632653X-RAY DIFFRACTION99.6784565916
1.9413-1.98650.2436633167441300.2068787854692635X-RAY DIFFRACTION99.6755587599
1.9865-2.03620.2746827446791530.1968125436352578X-RAY DIFFRACTION99.5988329686
2.0362-2.09120.2213437281581200.179642054672628X-RAY DIFFRACTION99.6013048206
2.0912-2.15280.1846129018481540.1749212542608X-RAY DIFFRACTION99.8192988797
2.1528-2.22220.2012522358771410.1772494583672655X-RAY DIFFRACTION100
2.2222-2.30170.2386644948461190.1884239191362632X-RAY DIFFRACTION100
2.3017-2.39380.2334213552111400.1844937044572641X-RAY DIFFRACTION100
2.3938-2.50270.2033739995231650.2068321071442600X-RAY DIFFRACTION100
2.5027-2.63470.2489621970731040.191172798232643X-RAY DIFFRACTION100
2.6347-2.79970.2099160135531700.204057443232596X-RAY DIFFRACTION100
2.7997-3.01580.2735158889531430.2048356416152638X-RAY DIFFRACTION99.964054637
3.0158-3.31920.2163044354451410.1799531565462639X-RAY DIFFRACTION100
3.3192-3.79920.2034533318471390.1605757749432598X-RAY DIFFRACTION100
3.7992-4.78550.1917204502951770.1717478650422603X-RAY DIFFRACTION99.9281092739
4.7855-41.85080.1866078204671420.1943841548722631X-RAY DIFFRACTION99.8200143988

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