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- PDB-3t0m: Small-molecule inhibitors of 14-3-3 protein-protein interactions ... -

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Basic information

Entry
Database: PDB / ID: 3t0m
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 localization of FOXO transcription factors / keratinocyte proliferation / phosphoserine residue binding / Activation of BAD and translocation to mitochondria / negative regulation of keratinocyte proliferation ...regulation of epidermal cell division / protein kinase C inhibitor activity / positive regulation of epidermal cell differentiation / keratinocyte development / keratinization / 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 / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / protein kinase A signaling / negative regulation of stem cell proliferation / SARS-CoV-1 targets host intracellular signalling and regulatory pathways / RHO GTPases activate PKNs / protein export from nucleus / negative regulation of innate immune response / protein sequestering activity / 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 / negative regulation of cysteine-type endopeptidase activity involved in apoptotic process / intrinsic apoptotic signaling pathway in response to DNA damage / 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-2CT / 14-3-3 protein sigma
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.62 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.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)27,1819
Polymers26,4861
Non-polymers6958
Water5,999333
1
A: 14-3-3 protein sigma
hetero molecules

A: 14-3-3 protein sigma
hetero molecules


Theoretical massNumber of molelcules
Total (without water)54,36218
Polymers52,9722
Non-polymers1,39116
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_555x,-y,-z1
Buried area4020 Å2
ΔGint-74 kcal/mol
Surface area22560 Å2
MethodPISA
Unit cell
Length a, b, c (Å)82.090, 112.300, 62.370
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-503-

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, 341 molecules

#2: Chemical ChemComp-2CT / (2-{2-[(2,5-dimethoxyphenyl)amino]-2-oxoethoxy}phenyl)phosphonic acid


Mass: 367.290 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H18NO7P
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


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


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#5: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Mg
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 333 / 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: 2

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Sample preparation

CrystalDensity Matthews: 2.71 Å3/Da / Density % sol: 54.67 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 0.095M HEPES Na salt, 0.19M calcium chloride, 5% glycerol, 25.6% PEG 400, pH 7.5, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

Diffraction
IDMean temperature (K)Crystal-ID
11001
21001
Diffraction source
SourceSiteBeamlineTypeIDWavelength (Å)
SYNCHROTRONSLS X10SA10.9778
ROTATING ANODERIGAKU MICROMAX-007 HF21.5418
Detector
TypeIDDetectorDateDetails
DECTRIS PILATUS 6M1PIXELMay 20, 2011
MAR scanner 345 mm plate2IMAGE PLATEApr 14, 2011Multilayer mirrors (VariMax)
Radiation
IDMonochromatorProtocolMonochromatic (M) / Laue (L)Scattering typeWavelength-ID
1Si(111) monochromator (horizontal), dynamically bendable mirror (vertical)SINGLE WAVELENGTHMx-ray1
2SINGLE WAVELENGTHMx-ray1
Radiation wavelength
IDWavelength (Å)Relative weight
10.97781
21.54181
ReflectionResolution: 1.62→45.42 Å / Num. all: 37003 / Num. obs: 36467 / % possible obs: 98.6 % / Observed criterion σ(F): -3 / Observed criterion σ(I): -3 / Redundancy: 6.73 % / Biso Wilson estimate: 24.424 Å2 / Rmerge(I) obs: 0.09 / Net I/σ(I): 13.87
Reflection shell

Diffraction-ID: 1,2

Resolution (Å)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. unique allNum. unique obs% possible all
1.62-1.70.3884.04219904759475996.7
1.7-1.80.2865.28219284779477996.2
1.8-20.2388.48467417084708497.8
2-2.30.14314.58548386707670799.9
2.3-2.60.10218.99314583980398099.9
2.6-30.08621.86247293130313099.9
3-40.0725.55252333418341899.8
4-60.06427.52129771801180199.9
6-80.06227.13321445645699.3
8-100.04929.781256166166100
10-120.05428.335257676100
12-45.420.0527.6674511111194.9

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation2.5 Å45.42 Å
Translation2.5 Å45.42 Å

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Processing

Software
NameVersionClassificationNB
XSCALEdata scaling
PHASER2.2.1phasing
REFMACrefinement
PDB_EXTRACT3.1data extraction
XDSdata scaling
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.62→45.42 Å / Cor.coef. Fo:Fc: 0.966 / Cor.coef. Fo:Fc free: 0.946 / WRfactor Rfree: 0.1983 / WRfactor Rwork: 0.1574 / Occupancy max: 1 / Occupancy min: 0.12 / FOM work R set: 0.8968 / SU B: 1.468 / SU ML: 0.052 / SU R Cruickshank DPI: 0.0807 / SU Rfree: 0.087 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.087 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.1978 1824 5 %RANDOM
Rwork0.1552 ---
all0.1573 34642 --
obs0.1573 34642 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: 66.54 Å2 / Biso mean: 20.171 Å2 / Biso min: 3.33 Å2
Baniso -1Baniso -2Baniso -3
1-0.87 Å20 Å20 Å2
2---0.38 Å20 Å2
3----0.49 Å2
Refinement stepCycle: LAST / Resolution: 1.62→45.42 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1807 0 42 333 2182
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0260.0222187
X-RAY DIFFRACTIONr_angle_refined_deg2.2232.0113013
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.6565313
X-RAY DIFFRACTIONr_dihedral_angle_2_deg40.17624.673107
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.70715439
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.4291518
X-RAY DIFFRACTIONr_chiral_restr0.1640.2331
X-RAY DIFFRACTIONr_gen_planes_refined0.0120.021695
X-RAY DIFFRACTIONr_mcbond_it1.4051.51290
X-RAY DIFFRACTIONr_mcangle_it2.30622125
X-RAY DIFFRACTIONr_scbond_it3.6653897
X-RAY DIFFRACTIONr_scangle_it5.8754.5841
LS refinement shellResolution: 1.62→1.662 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.248 131 -
Rwork0.195 2489 -
all-2620 -
obs-2620 100 %

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