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- PDB-6sip: Fragment AZ-011 binding at the p53pT387/14-3-3 sigma interface -

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Basic information

Entry
Database: PDB / ID: 6sip
TitleFragment AZ-011 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 / 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 / p53-like tetramerisation domain superfamily / p53/RUNT-type transcription factor, DNA-binding domain superfamily / Delta-Endotoxin; domain 1 / 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
7-methoxy-1-benzothiophene-2-carboximidamide / Cellular tumor antigen p53 / 14-3-3 protein sigma
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.6004470265 Å
AuthorsLeysen, S. / Wolter, M. / Guillory, X. / 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
DepositionAug 10, 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.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_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.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 / 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)28,2836
Polymers27,9922
Non-polymers2904
Water6,125340
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)56,56612
Polymers55,9854
Non-polymers5818
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_555x,-y,-z1
Buried area5810 Å2
ΔGint-72 kcal/mol
Surface area22780 Å2
MethodPISA
Unit cell
Length a, b, c (Å)82.121, 112.570, 62.684
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

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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, 344 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-LFB / 7-methoxy-1-benzothiophene-2-carboximidamide


Mass: 206.264 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H10N2OS / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 340 / 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: 2.64 Å3/Da / Density % sol: 53.34 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop
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: May 2, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 1.6→62.68 Å / Num. obs: 29038 / % possible obs: 74.8 % / Redundancy: 3.1 % / Biso Wilson estimate: 12.2248090387 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.026 / Net I/σ(I): 34.3
Reflection shellResolution: 1.6→1.69 Å / Redundancy: 1.2 % / Mean I/σ(I) obs: 6.7 / Num. unique obs: 1460 / CC1/2: 0.971 / % possible all: 26.1

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Processing

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

5moc


Resolution: 1.6004470265→19.9296097901 Å / SU ML: 0.128115032053 / Cross valid method: FREE R-VALUE / σ(F): 1.34879926691 / Phase error: 19.3000125847
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.19635890983 1373 4.73627927835 %
Rwork0.161686796033 27616 -
obs0.163348926018 28989 75.0038809832 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 15.4714960146 Å2
Refinement stepCycle: LAST / Resolution: 1.6004470265→19.9296097901 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1889 0 17 340 2246
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.005223197085492043
X-RAY DIFFRACTIONf_angle_d0.7876979325872780
X-RAY DIFFRACTIONf_chiral_restr0.0409124488376307
X-RAY DIFFRACTIONf_plane_restr0.00419017156043361
X-RAY DIFFRACTIONf_dihedral_angle_d13.31101845481291
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.6004470265-1.65760.241293469072290.180537846313704X-RAY DIFFRACTION19.0885416667
1.6576-1.7240.230912299367870.173179585371847X-RAY DIFFRACTION50.9483667018
1.724-1.80240.1967063541431300.1675526652032654X-RAY DIFFRACTION72.8986645719
1.8024-1.89730.2078011815521950.1657443176373282X-RAY DIFFRACTION90.7832898172
1.8973-2.01610.1931497209551930.1592494970613611X-RAY DIFFRACTION99.1399530884
2.0161-2.17160.1917893414621170.1536729757852688X-RAY DIFFRACTION72.8193146417
2.1716-2.38980.1769156634531510.1536971599422909X-RAY DIFFRACTION79.6875
2.3898-2.73480.1857173070371410.1610205742093059X-RAY DIFFRACTION82.6873385013
2.7348-3.44270.2256603884341580.1626615210523554X-RAY DIFFRACTION99.7313272434
3.4427-19.92960979010.1859689859111720.164208035693308X-RAY DIFFRACTION89.6676114404

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