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

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Basic information

Entry
Database: PDB / ID: 4dhp
TitleSmall-molecule inhibitors of 14-3-3 protein-protein interactions from virtual screening
Components14-3-3 protein sigma
KeywordsPROTEIN BINDING/INHIBITOR / 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 / 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 / protein sequestering activity / positive regulation of cell adhesion / 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 / stem cell proliferation / positive regulation of protein export from nucleus / 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-Y07 / 14-3-3 protein sigma
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.75 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)27,19610
Polymers26,5021
Non-polymers6949
Water6,954386
1
A: 14-3-3 protein sigma
hetero molecules

A: 14-3-3 protein sigma
hetero molecules


Theoretical massNumber of molelcules
Total (without water)54,39220
Polymers53,0042
Non-polymers1,38818
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_555x,-y,-z1
Buried area3720 Å2
ΔGint-86 kcal/mol
Surface area22550 Å2
MethodPISA
Unit cell
Length a, b, c (Å)82.250, 112.230, 62.420
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

21A-761-

HOH

31A-764-

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: 26501.865 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): ROSETTA DE3 / References: UniProt: P31947

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Non-polymers , 5 types, 395 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-Y07 / [2-(2-{[2-chloro-5-(trifluoromethyl)phenyl]amino}-2-oxoethoxy)phenyl]phosphonic acid


Mass: 409.681 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H12ClF3NO5P
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 386 / 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: 2.72 Å3/Da / Density % sol: 54.74 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 0.095M HEPES Na, 0.19M calcium chloride, 5% glycerol, 26% PEG400, pH 7.5, VAPOR DIFFUSION, HANGING 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: Dec 6, 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: 1.75→19.53 Å / Num. all: 28885 / Num. obs: 28885 / % possible obs: 97.9 % / Observed criterion σ(F): -3 / Observed criterion σ(I): -3 / Redundancy: 8.13 % / Biso Wilson estimate: 21.219 Å2 / Rmerge(I) obs: 0.066 / Net I/σ(I): 28.26
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
1.75-1.850.2497.27220634451426895.9
1.85-20.16310.52258545148498496.8
2-2.20.08917.51248174876476697.7
2.2-2.40.12926.61333613413334397.9
2.4-2.70.10432.62376733376334399
2.7-30.07540.32244552189216999.1
3-40.04656.22385193436342599.7
4-60.03764.89199541801179999.9
6-80.03764.174924461461100
8-100.0376.841744167167100
10-120.02777.487326575100
120.02776.148181178572.6

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Phasing

PhasingMethod: molecular replacement
Phasing MRRfactor: 29.44 / Model details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation2.5 Å19.53 Å
Translation2.5 Å19.53 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: 1.75→19.53 Å / Cor.coef. Fo:Fc: 0.962 / Cor.coef. Fo:Fc free: 0.934 / WRfactor Rfree: 0.18 / WRfactor Rwork: 0.1445 / Occupancy max: 1 / Occupancy min: 0.2 / FOM work R set: 0.8904 / SU B: 1.829 / SU ML: 0.06 / SU R Cruickshank DPI: 0.1028 / SU Rfree: 0.1048 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.103 / ESU R Free: 0.105 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.196 1445 5 %RANDOM
Rwork0.1537 ---
all0.1558 28885 --
obs0.1558 28885 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: 65.8 Å2 / Biso mean: 15.6588 Å2 / Biso min: 2 Å2
Baniso -1Baniso -2Baniso -3
1-0.54 Å20 Å20 Å2
2---0.03 Å20 Å2
3----0.51 Å2
Refinement stepCycle: LAST / Resolution: 1.75→19.53 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1799 0 39 386 2224
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0222143
X-RAY DIFFRACTIONr_angle_refined_deg1.4882.0132946
X-RAY DIFFRACTIONr_dihedral_angle_1_deg13.3295.131305
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.69324.904104
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.40615425
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.4781516
X-RAY DIFFRACTIONr_chiral_restr0.1020.2323
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.021657
X-RAY DIFFRACTIONr_mcbond_it0.8111.51269
X-RAY DIFFRACTIONr_mcangle_it1.42322077
X-RAY DIFFRACTIONr_scbond_it2.4683874
X-RAY DIFFRACTIONr_scangle_it3.9494.5830
LS refinement shellResolution: 1.75→1.795 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.252 103 -
Rwork0.202 1941 -
all-2044 -
obs--100 %

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