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- PDB-5exa: Small-molecule stabilization of the 14-3-3/Gab2 PPI interface -

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Basic information

Entry
Database: PDB / ID: 5exa
TitleSmall-molecule stabilization of the 14-3-3/Gab2 PPI interface
Components
  • 14-3-3 protein zeta/delta
  • GRB2-associated-binding protein 2
KeywordsSIGNALING PROTEIN / 14-3-3 / GAB2 / Protein / Diphosphorylation
Function / homology
Function and homology information


synaptic target recognition / Golgi reassembly / positive regulation of mast cell degranulation / NOTCH4 Activation and Transmission of Signal to the Nucleus / establishment of Golgi localization / STAT5 Activation / respiratory system process / regulation of synapse maturation / tube formation / phosphatidylinositol-3,4-bisphosphate binding ...synaptic target recognition / Golgi reassembly / positive regulation of mast cell degranulation / NOTCH4 Activation and Transmission of Signal to the Nucleus / establishment of Golgi localization / STAT5 Activation / respiratory system process / regulation of synapse maturation / tube formation / phosphatidylinositol-3,4-bisphosphate binding / transmembrane receptor protein tyrosine kinase adaptor activity / Rap1 signalling / Signaling by cytosolic FGFR1 fusion mutants / Interleukin-15 signaling / negative regulation of protein localization to nucleus / KSRP (KHSRP) binds and destabilizes mRNA / GP1b-IX-V activation signalling / STAT5 activation downstream of FLT3 ITD mutants / phosphatidylinositol-3,4,5-trisphosphate binding / RET signaling / Regulation of localization of FOXO transcription factors / Interleukin-3, Interleukin-5 and GM-CSF signaling / PI3K Cascade / phosphoserine residue binding / Activation of BAD and translocation to mitochondria / Role of LAT2/NTAL/LAB on calcium mobilization / Interleukin receptor SHC signaling / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / protein targeting / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / regulation of ERK1 and ERK2 cascade / Signaling by CSF3 (G-CSF) / cellular response to glucose starvation / SARS-CoV-1 targets host intracellular signalling and regulatory pathways / RHO GTPases activate PKNs / Signaling by FLT3 ITD and TKD mutants / negative regulation of TORC1 signaling / Signaling by FLT3 fusion proteins / FLT3 Signaling / Transcriptional and post-translational regulation of MITF-M expression and activity / ERK1 and ERK2 cascade / osteoclast differentiation / protein sequestering activity / negative regulation of innate immune response / hippocampal mossy fiber to CA3 synapse / Translocation of SLC2A4 (GLUT4) to the plasma membrane / TP53 Regulates Metabolic Genes / phosphatidylinositol 3-kinase/protein kinase B signal transduction / Deactivation of the beta-catenin transactivating complex / lung development / Negative regulation of NOTCH4 signaling / Signaling by SCF-KIT / regulation of protein stability / Signaling by CSF1 (M-CSF) in myeloid cells / Constitutive Signaling by Aberrant PI3K in Cancer / intracellular protein localization / melanosome / PIP3 activates AKT signaling / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / angiogenesis / DNA-binding transcription factor binding / vesicle / blood microparticle / transmembrane transporter binding / protein phosphorylation / cadherin binding / protein domain specific binding / membrane raft / focal adhesion / positive regulation of cell population proliferation / ubiquitin protein ligase binding / negative regulation of apoptotic process / protein kinase binding / glutamatergic synapse / negative regulation of transcription by RNA polymerase II / signal transduction / extracellular space / RNA binding / extracellular exosome / nucleoplasm / identical protein binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
GRB2-associated-binding protein 1-4-like / 14-3-3 domain / Delta-Endotoxin; domain 1 / 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 ...GRB2-associated-binding protein 1-4-like / 14-3-3 domain / Delta-Endotoxin; domain 1 / 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 / PH domain / PH domain profile. / Pleckstrin homology domain. / Pleckstrin homology domain / PH-like domain superfamily / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
Fusicoccin A-THF derivative / BENZOIC ACID / 14-3-3 protein zeta/delta / GRB2-associated-binding protein 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.95 Å
AuthorsBier, D. / Ottmann, C.
CitationJournal: Chemmedchem / Year: 2016
Title: Small-Molecule Stabilization of the 14-3-3/Gab2 Protein-Protein Interaction (PPI) Interface.
Authors: Bier, D. / Bartel, M. / Sies, K. / Halbach, S. / Higuchi, Y. / Haranosono, Y. / Brummer, T. / Kato, N. / Ottmann, C.
History
DepositionNov 23, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0May 4, 2016Provider: repository / Type: Initial release
Revision 1.1Dec 19, 2018Group: Data collection / Derived calculations / Category: struct_conn
Revision 1.2Nov 6, 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 / struct_conn / struct_conn_type
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_asym_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_asym_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_conn.ptnr2_label_seq_id / _struct_conn_type.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 zeta/delta
B: 14-3-3 protein zeta/delta
C: GRB2-associated-binding protein 2
D: GRB2-associated-binding protein 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,7369
Polymers55,3944
Non-polymers1,3425
Water3,477193
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5140 Å2
ΔGint-22 kcal/mol
Surface area23100 Å2
MethodPISA
Unit cell
Length a, b, c (Å)72.000, 83.090, 111.150
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Protein / Protein/peptide , 2 types, 4 molecules ABCD

#1: Protein 14-3-3 protein zeta/delta / Protein kinase C inhibitor protein 1 / KCIP-1


Mass: 26316.764 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: YWHAZ / Production host: Escherichia coli (E. coli) / References: UniProt: P63104
#2: Protein/peptide GRB2-associated-binding protein 2 / GRB2-associated binder 2 / Growth factor receptor bound protein 2-associated protein 2 / pp100


Mass: 1380.467 Da / Num. of mol.: 2 / Fragment: UNP residues 387-395 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: Q9UQC2

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Non-polymers , 4 types, 198 molecules

#3: Chemical ChemComp-5SO / Fusicoccin A-THF derivative


Mass: 536.697 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C30H48O8
#4: Chemical ChemComp-BEZ / BENZOIC ACID


Mass: 122.121 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C7H6O2
#5: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg / Source: (synth.) Homo sapiens (human)
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 193 / 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: 3.03 Å3/Da / Density % sol: 59.37 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, hanging drop
Details: 0.17 M ammonium acetate, 0.085 M sodium citrate pH 5.6, 25.5% (w/v) PEG 4000, 15% (v/v) glycerol.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 10, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionHighest resolution: 1.95 Å / Num. obs: 49195 / % possible obs: 99.8 % / Observed criterion σ(I): -3 / Biso Wilson estimate: 36.714 Å2 / Rmerge F obs: 0.064 / Rmerge(I) obs: 0.045 / Rrim(I) all: 0.051 / Χ2: 0.995 / Net I/σ(I): 21.35 / Num. measured all: 247516
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Highest resolution (Å)Rmerge F obsRmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsRrim(I) all% possible all
1.95-20.3790.4144.2918766356535640.46100
2-2.050.3150.335.3316656317631740.36899.9
2.05-2.10.2440.2526.8715126292929300.281100
2.1-2.20.1780.1849.0125726508150750.20699.9
2.2-2.30.1350.13111.6520305424642400.14899.9
2.3-2.40.0970.10314.8218026356035550.11599.9
2.4-2.50.0790.09116.6815879303530320.10299.9
2.5-2.60.0640.07619.6113444258725850.08599.9
2.6-2.70.0530.06622.1911413220922070.07499.9
2.7-2.80.0460.05724.019660191419120.06499.9
2.8-2.90.0410.0526.367834166916650.05699.8
2.9-30.0390.04728.56890145814560.05399.9
3-40.0240.03538.5639739788878540.03999.6
40.0170.02744.7228052598759460.03199.3

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation2.5 Å48.87 Å
Translation2.5 Å48.87 Å

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Processing

Software
NameVersionClassification
REFMAC5.5.0102refinement
XSCALEdata scaling
PHASER2.3.0phasing
PDB_EXTRACT3.15data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.95→48.87 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.938 / WRfactor Rfree: 0.2372 / WRfactor Rwork: 0.1987 / FOM work R set: 0.8568 / SU B: 3.085 / SU ML: 0.091 / SU R Cruickshank DPI: 0.1448 / SU Rfree: 0.1376 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.145 / ESU R Free: 0.138 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.234 2460 5 %RANDOM
Rwork0.1983 ---
obs0.2001 46735 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: 269.21 Å2 / Biso mean: 31.043 Å2 / Biso min: 13.87 Å2
Baniso -1Baniso -2Baniso -3
1--1 Å20 Å20 Å2
2--1.2 Å20 Å2
3----0.2 Å2
Refinement stepCycle: final / Resolution: 1.95→48.87 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3815 0 95 193 4103
Biso mean--40.25 39.79 -
Num. residues----479
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0250.0223974
X-RAY DIFFRACTIONr_angle_refined_deg2.3452.0055371
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.825477
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.13825.132189
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.38415731
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.4771526
X-RAY DIFFRACTIONr_chiral_restr0.2430.2607
X-RAY DIFFRACTIONr_gen_planes_refined0.010.022922
X-RAY DIFFRACTIONr_mcbond_it1.3531.52398
X-RAY DIFFRACTIONr_mcangle_it2.49623834
X-RAY DIFFRACTIONr_scbond_it431576
X-RAY DIFFRACTIONr_scangle_it6.5034.51536
LS refinement shellResolution: 1.95→2.001 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.29 180 -
Rwork0.236 3419 -
all-3599 -
obs--100 %

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