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- PDB-4dhu: Small-molecule inhibitors of 14-3-3 protein-protein interactions ... -

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Basic information

Entry
Database: PDB / ID: 4dhu
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 / PHOSPHOPROTEIN BINDING / 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 / Regulation of localization of FOXO transcription factors / keratinocyte proliferation / phosphoserine residue binding / Activation of BAD and translocation to mitochondria ...regulation of epidermal cell division / protein kinase C inhibitor activity / positive regulation of epidermal cell differentiation / keratinocyte development / keratinization / regulation of cell-cell adhesion / 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 / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / negative regulation of stem cell proliferation / SARS-CoV-1 targets host intracellular signalling and regulatory pathways / positive regulation of protein localization / RHO GTPases activate PKNs / protein kinase A signaling / protein sequestering activity / protein export from nucleus / negative regulation of innate immune response / positive regulation of cell adhesion / TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest / release of cytochrome c from mitochondria / positive regulation of protein export from nucleus / stem cell proliferation / Translocation of SLC2A4 (GLUT4) to the plasma membrane / TP53 Regulates Metabolic Genes / negative regulation of protein kinase activity / intrinsic apoptotic signaling pathway in response to DNA damage / 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-0KH / 14-3-3 protein sigma
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.67 Å
AuthorsThiel, P. / Roeglin, L. / Kohlbacher, O. / 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
DepositionJan 30, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 31, 2013Provider: repository / Type: Initial release
Revision 1.1Sep 4, 2013Group: Database references
Revision 1.2Nov 20, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature / 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_leaving_atom_flag / _struct_conn.pdbx_ptnr1_label_alt_id / _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)27,16310
Polymers26,5021
Non-polymers6619
Water7,332407
1
A: 14-3-3 PROTEIN SIGMA
hetero molecules

A: 14-3-3 PROTEIN SIGMA
hetero molecules


Theoretical massNumber of molelcules
Total (without water)54,32520
Polymers53,0042
Non-polymers1,32118
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_555x,-y,-z1
Buried area3390 Å2
ΔGint-92 kcal/mol
Surface area22980 Å2
MethodPISA
Unit cell
Length a, b, c (Å)82.320, 112.460, 62.500
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-301-

MG

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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: 26501.865 Da / Num. of mol.: 1 / Fragment: UNP resiudes 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): ROSETTA DE3 / References: UniProt: P31947

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Non-polymers , 5 types, 416 molecules

#2: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: Mg
#3: Chemical ChemComp-CL / CHLORIDE ION


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


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-0KH / (2-{2-[(2,3-dichlorophenyl)amino]-2-oxoethoxy}phenyl)phosphonic acid


Mass: 376.129 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H12Cl2NO5P
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 407 / 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: 2.73 Å3/Da / Density % sol: 54.96 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7.1
Details: 0.095M HEPES Na, 0.19M calcium chloride, 5% glycerol, 27% PEG400, pH 7.1, VAPOR DIFFUSION, SITTING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.5418 Å
DetectorType: MAR scanner 345 mm plate / Detector: IMAGE PLATE / Date: Nov 22, 2011 / Details: mirrors
RadiationMonochromator: CURVED MULTILAYER MIRRORS / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.67→19.547 Å / Num. all: 33635 / Num. obs: 33635 / % possible obs: 98.8 % / Observed criterion σ(F): -3 / Observed criterion σ(I): -3 / Redundancy: 7.8 % / Biso Wilson estimate: 21.938 Å2 / Rmerge(I) obs: 0.032 / Net I/σ(I): 45.03
Reflection shell

Diffraction-ID: 1

Resolution (Å)Highest resolution (Å)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. unique allNum. unique obs% possible all
1.67-1.750.1213.16211044129412994.1
1.75-1.850.09316.96239264422442298.8
1.85-20.06423.49281365163516399.4
2-2.20.0435.29267604864486499.6
2.2-2.40.04851.55342423418341899.9
2.4-2.70.0461.143765533893389100
2.7-30.03370.762462822032203100
3-40.02588.083851434483448100
4-60.02496.211977818121812100
6-80.02495.29480046046099.6
8-100.02196.711558167167100
10-120.02293.41636747498.7
120.02493.75740868672.9

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Processing

Software
NameVersionClassificationNB
XSCALEdata scaling
REFMACrefinement
PDB_EXTRACT3.1data extraction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.67→19.547 Å / Cor.coef. Fo:Fc: 0.972 / Cor.coef. Fo:Fc free: 0.954 / WRfactor Rfree: 0.1762 / WRfactor Rwork: 0.1309 / Occupancy max: 1 / Occupancy min: 0.2 / FOM work R set: 0.9117 / SU B: 2.846 / SU ML: 0.045 / SU R Cruickshank DPI: 0.1165 / SU Rfree: 0.0842 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.116 / ESU R Free: 0.084 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.1762 1682 5 %RANDOM
Rwork0.131 ---
all0.1333 33635 --
obs0.1333 33634 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: 59.28 Å2 / Biso mean: 16.9125 Å2 / Biso min: 4.48 Å2
Baniso -1Baniso -2Baniso -3
1-0.62 Å20 Å20 Å2
2---0.17 Å20 Å2
3----0.45 Å2
Refinement stepCycle: LAST / Resolution: 1.67→19.547 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1799 0 36 407 2242
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0190.0222180
X-RAY DIFFRACTIONr_angle_refined_deg1.71823007
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.4925320
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.7725.091110
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.08215439
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.4191516
X-RAY DIFFRACTIONr_chiral_restr0.1190.2333
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.021698
X-RAY DIFFRACTIONr_mcbond_it1.4761.51296
X-RAY DIFFRACTIONr_mcangle_it2.26522133
X-RAY DIFFRACTIONr_scbond_it3.4573884
X-RAY DIFFRACTIONr_scangle_it5.24.5826
X-RAY DIFFRACTIONr_rigid_bond_restr2.01332180
X-RAY DIFFRACTIONr_sphericity_free7.7683421
X-RAY DIFFRACTIONr_sphericity_bonded3.96432104
LS refinement shellResolution: 1.671→1.714 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.246 115 -
Rwork0.168 2191 -
all-2306 -
obs--100 %

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