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- PDB-6s9q: Fragment AZ-004 binding at a primary and secondary site in a p53p... -

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Basic information

Entry
Database: PDB / ID: 6s9q
TitleFragment AZ-004 binding at a primary and secondary site in a p53pT387/14-3-3 complex
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 / negative regulation of mitophagy / mRNA transcription / circadian behavior / bone marrow development / germ cell nucleus / regulation of mitochondrial membrane permeability involved in apoptotic process / histone deacetylase regulator activity / regulation of DNA damage response, signal transduction by p53 class mediator / 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 / : / 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 / regulation of epidermal cell division / protein kinase C inhibitor activity / B cell lineage commitment / thymocyte apoptotic process / positive regulation of epidermal cell differentiation / keratinocyte development / TP53 Regulates Transcription of Caspase Activators and Caspases / negative regulation of DNA replication / keratinization / cardiac septum morphogenesis / entrainment of circadian clock by photoperiod / PI5P Regulates TP53 Acetylation / regulation of cell-cell adhesion / negative regulation of telomere maintenance via telomerase / necroptotic process / positive regulation of release of cytochrome c from mitochondria / Zygotic genome activation (ZGA) / Association of TriC/CCT with target proteins during biosynthesis / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / TFIID-class transcription factor complex binding / T cell proliferation involved in immune response / SUMOylation of transcription factors / rRNA transcription / cAMP/PKA signal transduction / 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 / Regulation of localization of FOXO transcription factors / positive regulation of execution phase of apoptosis / Transcriptional Regulation by VENTX / keratinocyte proliferation / general transcription initiation factor binding / replicative senescence / phosphoserine residue binding / cellular response to actinomycin D / cellular response to UV-C / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / neuroblast proliferation / Activation of BAD and translocation to mitochondria / hematopoietic stem cell differentiation / positive regulation of RNA polymerase II transcription preinitiation complex assembly / response to X-ray / negative regulation of keratinocyte proliferation / negative regulation of reactive oxygen species metabolic process / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / DNA damage response, signal transduction by p53 class mediator / chromosome organization / establishment of skin barrier / viral process / Pyroptosis / embryonic organ development / negative regulation of protein localization to plasma membrane / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / cis-regulatory region sequence-specific DNA binding / type II interferon-mediated signaling pathway / glial cell proliferation / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / somitogenesis
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 / 14-3-3 domain / 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
4-methyl-5-phenyl-thiophene-2-carboximidamide / Cellular tumor antigen p53 / 14-3-3 protein sigma
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.69 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
DepositionJul 15, 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
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)30,3496
Polymers29,6602
Non-polymers6894
Water3,225179
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)60,69812
Polymers59,3204
Non-polymers1,3788
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_555x,-y,-z1
Buried area5470 Å2
ΔGint-52 kcal/mol
Surface area22810 Å2
MethodPISA
Unit cell
Length a, b, c (Å)82.105, 111.850, 62.703
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

#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


Mass: 1449.520 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P04637
#3: Chemical ChemComp-L1T / 4-methyl-5-phenyl-thiophene-2-carboximidamide


Mass: 216.302 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C12H12N2S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: Ca
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 179 / 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: 2.66 Å3/Da / Density % sol: 53.81 %
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: Jul 7, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 1.69→62.7 Å / Num. obs: 28198 / % possible obs: 86 % / Redundancy: 6.4 % / Biso Wilson estimate: 14.58 Å2 / CC1/2: 0.992 / Rmerge(I) obs: 0.138 / Rpim(I) all: 0.059 / Rrim(I) all: 0.151 / Net I/σ(I): 13.5
Reflection shellResolution: 1.69→1.78 Å / Redundancy: 4.7 % / Rmerge(I) obs: 0.857 / Mean I/σ(I) obs: 2.2 / Num. unique obs: 2031 / CC1/2: 0.705 / Rpim(I) all: 0.405 / Rrim(I) all: 0.953 / % possible all: 43.5

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Processing

Software
NameClassification
REFMACrefinement
PHENIXrefinement
MOSFLMdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5MOC

5moc


Resolution: 1.69→45.52 Å / SU ML: 0.1861 / Cross valid method: THROUGHOUT / σ(F): 1.94 / Phase error: 21.4915
RfactorNum. reflection% reflection
Rfree0.2256 1386 4.92 %
Rwork0.1926 --
obs0.1941 28174 85.6 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 16.4 Å2
Refinement stepCycle: LAST / Resolution: 1.69→45.52 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1873 0 46 179 2098
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00852048
X-RAY DIFFRACTIONf_angle_d1.03532778
X-RAY DIFFRACTIONf_chiral_restr0.0452301
X-RAY DIFFRACTIONf_plane_restr0.0058361
X-RAY DIFFRACTIONf_dihedral_angle_d3.40051697
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.69-1.750.3595710.26531202X-RAY DIFFRACTION38.99
1.75-1.820.2708880.23891729X-RAY DIFFRACTION56.48
1.82-1.90.2591220.22862580X-RAY DIFFRACTION83.06
1.9-20.22781660.20252925X-RAY DIFFRACTION94.87
2-2.120.21571580.18022943X-RAY DIFFRACTION95.09
2.12-2.290.2221620.1652988X-RAY DIFFRACTION95.86
2.29-2.520.19051530.15953009X-RAY DIFFRACTION96.55
2.52-2.880.21271460.17293063X-RAY DIFFRACTION97.39
2.88-3.630.21621500.18163127X-RAY DIFFRACTION98.38
3.63-45.520.23931700.22673222X-RAY DIFFRACTION97.86

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