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- PDB-3t0l: Small-molecule inhibitors of 14-3-3 protein-protein interactions ... -

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Basic information

Entry
Database: PDB / ID: 3t0l
TitleSmall-molecule inhibitors of 14-3-3 protein-protein interactions from virtual screening
Components14-3-3 protein sigma
KeywordsPROTEIN BINDING/INHIBITOR / Helical protein / Adapter protein / Protein-protein interaction / PROTEIN BINDING-INHIBITOR complex
Function / homology
Function and homology information


regulation of epidermal cell division / protein kinase C inhibitor activity / positive regulation of epidermal cell differentiation / keratinocyte development / keratinization / regulation of cell-cell adhesion / cAMP/PKA signal transduction / Regulation of localization of FOXO transcription factors / keratinocyte proliferation / phosphoserine residue binding ...regulation of epidermal cell division / protein kinase C inhibitor activity / positive regulation of epidermal cell differentiation / keratinocyte development / keratinization / regulation of cell-cell adhesion / cAMP/PKA signal transduction / Regulation of localization of FOXO transcription factors / keratinocyte proliferation / phosphoserine residue binding / Activation of BAD and translocation to mitochondria / negative regulation of keratinocyte proliferation / establishment of skin barrier / negative regulation of protein localization to plasma membrane / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / negative regulation of stem cell proliferation / SARS-CoV-1 targets host intracellular signalling and regulatory pathways / RHO GTPases activate PKNs / positive regulation of protein localization / positive regulation of cell adhesion / protein sequestering activity / negative regulation of innate immune response / protein export from nucleus / release of cytochrome c from mitochondria / TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest / positive regulation of protein export from nucleus / negative regulation of protein kinase activity / stem cell proliferation / Translocation of SLC2A4 (GLUT4) to the plasma membrane / TP53 Regulates Metabolic Genes / intrinsic apoptotic signaling pathway in response to DNA damage / intracellular protein localization / regulation of protein localization / positive regulation of cell growth / regulation of cell cycle / cadherin binding / protein kinase binding / negative regulation of transcription by RNA polymerase II / signal transduction / extracellular space / extracellular exosome / identical protein binding / nucleus / cytosol / cytoplasm
Similarity search - Function
14-3-3 domain / 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 domain / 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 / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-1CT / 14-3-3 protein sigma
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.6 Å
AuthorsThiel, P. / Ottmann, C.
CitationJournal: Chem.Commun.(Camb.) / Year: 2013
Title: Virtual screening and experimental validation reveal novel small-molecule inhibitors of 14-3-3 protein-protein interactions.
Authors: Thiel, P. / Roglin, L. / Meissner, N. / Hennig, S. / Kohlbacher, O. / Ottmann, C.
History
DepositionJul 20, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 26, 2012Provider: repository / Type: Initial release
Revision 1.1Sep 4, 2013Group: Database references
Revision 1.2Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_conn_angle / struct_conn / struct_ref_seq_dif / struct_site
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.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _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.value / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_ptnr2_label_alt_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_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_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,2009
Polymers26,4861
Non-polymers7148
Water6,017334
1
A: 14-3-3 protein sigma
hetero molecules

A: 14-3-3 protein sigma
hetero molecules


Theoretical massNumber of molelcules
Total (without water)54,40118
Polymers52,9722
Non-polymers1,42916
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_555x,-y,-z1
Buried area4080 Å2
ΔGint-76 kcal/mol
Surface area22740 Å2
MethodPISA
Unit cell
Length a, b, c (Å)82.440, 112.790, 62.650
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-238-

MG

21A-528-

HOH

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Components

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Protein , 1 types, 1 molecules A

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


Mass: 26485.865 Da / Num. of mol.: 1 / Fragment: UNP residues 1-231
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HME1, SFN / Plasmid: pPROEX HTB / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P31947

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Non-polymers , 5 types, 342 molecules

#2: Chemical ChemComp-1CT / [2-(2-oxo-2-{[2-(trifluoromethyl)phenyl]amino}ethoxy)phenyl]phosphonic acid


Mass: 375.236 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H13F3NO5P
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Cl
#5: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 334 / 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: 2.75 Å3/Da / Density % sol: 55.26 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.7
Details: 0.095M HEPES Na salt, 0.19M calcium chloride, 5% glycerol, 28% PEG 400, pH 7.7, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.9778 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 20, 2011
RadiationMonochromator: Si(111) monochromator (horizontal), dynamically bendable mirror (vertical)
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9778 Å / Relative weight: 1
ReflectionResolution: 1.6→45.62 Å / Num. all: 38904 / Num. obs: 38584 / % possible obs: 99.2 % / Observed criterion σ(F): -3 / Observed criterion σ(I): -3 / Redundancy: 8.78 % / Biso Wilson estimate: 27.168 Å2 / Rmerge(I) obs: 0.05 / Net I/σ(I): 23.88
Reflection shell

Diffraction-ID: 1

Resolution (Å)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. unique allNum. unique obs% possible all
1.6-1.70.4045.85540286363636399.4
1.7-1.80.2668.63446035042504299.8
1.8-20.14614.33662807322732299.8
2-2.50.06428.11851379604960499.3
2.5-30.04539.09373564262426298.7
3-40.03548.77299423422342298.6
4-60.03450.69147081775177597.3
6-80.03452.29389145145196.8
8-100.0356.25141715915997
10-120.02954.58616757596.2
12-45.620.03352.3184010910992.4

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Phasing

PhasingMethod: molecular replacement
Phasing MRRfactor: 25.95 / Model details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation2.5 Å45.62 Å
Translation2.5 Å45.62 Å

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Processing

Software
NameVersionClassificationNB
XSCALEdata scaling
PHASER2.1.4phasing
REFMACrefinement
PDB_EXTRACT3.1data extraction
XDSdata scaling
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.6→45.62 Å / Cor.coef. Fo:Fc: 0.969 / Cor.coef. Fo:Fc free: 0.962 / WRfactor Rfree: 0.1922 / WRfactor Rwork: 0.1574 / Occupancy max: 1 / Occupancy min: 0.3 / FOM work R set: 0.899 / SU B: 1.281 / SU ML: 0.046 / SU R Cruickshank DPI: 0.0773 / SU Rfree: 0.0799 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.08 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.1895 1930 5 %RANDOM
Rwork0.1568 ---
all0.1584 36654 --
obs0.1584 36654 100 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso max: 69.72 Å2 / Biso mean: 22.329 Å2 / Biso min: 9.85 Å2
Baniso -1Baniso -2Baniso -3
1-0.79 Å20 Å20 Å2
2---0.27 Å20 Å2
3----0.52 Å2
Refinement stepCycle: LAST / Resolution: 1.6→45.62 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1807 0 42 334 2183
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0210.0222180
X-RAY DIFFRACTIONr_angle_refined_deg1.9972.0043002
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.8535315
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.27224.954109
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.71215441
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.5631517
X-RAY DIFFRACTIONr_chiral_restr0.1420.2331
X-RAY DIFFRACTIONr_gen_planes_refined0.010.021687
X-RAY DIFFRACTIONr_mcbond_it1.1731.51295
X-RAY DIFFRACTIONr_mcangle_it2.01322129
X-RAY DIFFRACTIONr_scbond_it3.3263885
X-RAY DIFFRACTIONr_scangle_it5.4134.5827
LS refinement shellResolution: 1.6→1.642 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.227 142 -
Rwork0.192 2693 -
all-2835 -
obs-2835 100 %

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