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- PDB-8a62: Small molecule stabilizer (compound 2) for FOXO1 and 14-3-3 -

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Basic information

Entry
Database: PDB / ID: 8a62
TitleSmall molecule stabilizer (compound 2) for FOXO1 and 14-3-3
Components
  • 14-3-3 protein sigma
  • Forkhead box protein O1
KeywordsSTRUCTURAL PROTEIN / 14-3-3 / FOXO1 / Stabilization
Function / homology
Function and homology information


cellular response to hyperoxia / regulation of transcription initiation by RNA polymerase II / AKT-mediated inactivation of FOXO1A / FOXO-mediated transcription of cell cycle genes / AKT phosphorylates targets in the nucleus / positive regulation of smooth muscle cell apoptotic process / neuronal stem cell population maintenance / regulation of neural precursor cell proliferation / response to fatty acid / Regulation of FOXO transcriptional activity by acetylation ...cellular response to hyperoxia / regulation of transcription initiation by RNA polymerase II / AKT-mediated inactivation of FOXO1A / FOXO-mediated transcription of cell cycle genes / AKT phosphorylates targets in the nucleus / positive regulation of smooth muscle cell apoptotic process / neuronal stem cell population maintenance / regulation of neural precursor cell proliferation / response to fatty acid / Regulation of FOXO transcriptional activity by acetylation / negative regulation of stress-activated MAPK cascade / negative regulation of cardiac muscle hypertrophy in response to stress / regulation of reactive oxygen species metabolic process / cellular response to cold / protein acetylation / temperature homeostasis / regulation of epidermal cell division / protein kinase C inhibitor activity / negative regulation of fat cell differentiation / positive regulation of epidermal cell differentiation / keratinocyte development / keratinization / blood vessel development / FOXO-mediated transcription of cell death genes / Constitutive Signaling by AKT1 E17K in Cancer / fat cell differentiation / intracellular glucose homeostasis / regulation of cell-cell adhesion / Regulation of gene expression in beta cells / 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 / canonical Wnt signaling pathway / negative regulation of protein localization to plasma membrane / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / negative regulation of insulin secretion / negative regulation of stem cell proliferation / SARS-CoV-1 targets host intracellular signalling and regulatory pathways / RHO GTPases activate PKNs / energy homeostasis / positive regulation of protein localization / positive regulation of autophagy / positive regulation of gluconeogenesis / positive regulation of cell adhesion / cellular response to nitric oxide / 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 / protein phosphatase 2A binding / cellular response to starvation / 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 / promoter-specific chromatin binding / negative regulation of canonical Wnt signaling pathway / MAPK6/MAPK4 signaling / beta-catenin binding / chromatin DNA binding / autophagy / DNA-binding transcription repressor activity, RNA polymerase II-specific / cellular response to insulin stimulus / intrinsic apoptotic signaling pathway in response to DNA damage / positive regulation of protein catabolic process / intracellular protein localization / insulin receptor signaling pathway / regulation of protein localization / DNA-binding transcription activator activity, RNA polymerase II-specific / positive regulation of cell growth / cellular response to oxidative stress / Interleukin-4 and Interleukin-13 signaling / gene expression / sequence-specific DNA binding / nucleic acid binding / DNA-binding transcription factor activity, RNA polymerase II-specific / regulation of cell cycle / cadherin binding / positive regulation of apoptotic process / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / negative regulation of DNA-templated transcription / apoptotic process / ubiquitin protein ligase binding / DNA damage response / chromatin binding / regulation of transcription by RNA polymerase II / negative regulation of apoptotic process / protein kinase binding / chromatin / positive regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II
Similarity search - Function
: / FOXO protein, KIX-binding domain / KIX-binding domain of forkhead box O, CR2 / FOXO protein, transactivation domain / Transactivation domain of FOXO protein family / Fork head domain / Forkhead domain / Fork head domain profile. / FORKHEAD / Fork head domain conserved site 2 ...: / FOXO protein, KIX-binding domain / KIX-binding domain of forkhead box O, CR2 / FOXO protein, transactivation domain / Transactivation domain of FOXO protein family / Fork head domain / Forkhead domain / Fork head domain profile. / FORKHEAD / Fork head domain conserved site 2 / Fork head domain signature 2. / 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 / Winged helix DNA-binding domain superfamily / Winged helix-like DNA-binding domain superfamily / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-L7L / 14-3-3 protein sigma / Forkhead box protein O1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 Å
AuthorsKenanova, D.N. / Visser, E.J. / Virta, J. / Sijbesma, E. / Centorrino, F. / Zhong, M. / Vickery, H. / Neitz, J. / Brunsveld, L. / Ottmann, C. / Arkin, M.R.
Funding support Netherlands, 1items
OrganizationGrant numberCountry
Netherlands Organisation for Scientific Research (NWO)024.001.035 Netherlands
CitationJournal: Acs Cent.Sci. / Year: 2023
Title: A Systematic Approach to the Discovery of Protein-Protein Interaction Stabilizers.
Authors: Kenanova, D.N. / Visser, E.J. / Virta, J.M. / Sijbesma, E. / Centorrino, F. / Vickery, H.R. / Zhong, M. / Neitz, R.J. / Brunsveld, L. / Ottmann, C. / Arkin, M.R.
History
DepositionJun 16, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 26, 2023Provider: repository / Type: Initial release
Revision 1.1Jun 7, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Feb 7, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: 14-3-3 protein sigma
B: Forkhead box protein O1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,4605
Polymers27,9312
Non-polymers5293
Water6,557364
1
A: 14-3-3 protein sigma
B: Forkhead box protein O1
hetero molecules

A: 14-3-3 protein sigma
B: Forkhead box protein O1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,92110
Polymers55,8634
Non-polymers1,0586
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_555x,-y,-z1
Buried area5660 Å2
ΔGint-61 kcal/mol
Surface area23650 Å2
MethodPISA
Unit cell
Length a, b, c (Å)81.597, 111.503, 62.707
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221

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Components

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


Mass: 26542.914 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SFN, HME1 / Production host: Escherichia coli (E. coli) / References: UniProt: P31947
#2: Protein/peptide Forkhead box protein O1 / Forkhead box protein O1A / Forkhead in rhabdomyosarcoma


Mass: 1388.406 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: Q12778
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-L7L / (3~{S})-1-[3,5-bis(chloranyl)-4-oxidanyl-phenyl]carbonyl-~{N}-[2-[2-(dimethylamino)ethyldisulfanyl]ethyl]piperidine-3-carboxamide


Mass: 480.472 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H27Cl2N3O3S2 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 364 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
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: 2.55 Å3/Da / Density % sol: 51.85 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 0.095 M HEPES pH 7.5, 0.19 M CaCl2, 5% glycerol, 24% PEG 400

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: PETRA III, DESY / Beamline: P11 / Wavelength: 1.03322 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Nov 4, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.03322 Å / Relative weight: 1
ReflectionResolution: 1.6→45.41 Å / Num. obs: 512777 / % possible obs: 97.6 % / Redundancy: 13.8 % / CC1/2: 1 / Net I/σ(I): 39
Reflection shellResolution: 1.6→1.63 Å / Redundancy: 12.6 % / Num. unique obs: 1773 / CC1/2: 0.992

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
PDB_EXTRACT3.27data extraction
HKL-2000data reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4JC3

4jc3


Resolution: 1.6→45.41 Å / SU ML: 0.14 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 17.03 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1822 3636 5.11 %
Rwork0.1571 67464 -
obs0.1584 71100 97.44 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 59.7 Å2 / Biso mean: 17.2806 Å2 / Biso min: 1.58 Å2
Refinement stepCycle: final / Resolution: 1.6→45.41 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1937 0 43 364 2344
Biso mean--29.39 27.8 -
Num. residues----247
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 26

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.6-1.620.2121420.16472526266896
1.62-1.640.18631480.16162407255590
1.64-1.670.16951340.152592272697
1.67-1.690.20861270.15132569269697
1.69-1.720.20851420.15252582272497
1.72-1.750.20821700.16822594276497
1.75-1.780.19551350.16632539267497
1.78-1.810.23041320.16952649278198
1.81-1.840.20891620.172541270397
1.84-1.880.23521370.17382621275898
1.88-1.920.20541370.16132630276798
1.92-1.970.17231570.15762589274698
1.97-2.020.17491220.15422636275898
2.02-2.070.24451670.14862605277299
2.07-2.130.1791450.15522621276698
2.13-2.20.18481220.15292610273298
2.2-2.280.16421200.14122475259592
2.28-2.370.13961350.13992602273799
2.37-2.480.19171080.14872693280199
2.48-2.610.18011640.15332601276599
2.61-2.770.14761030.15792690279399
2.77-2.990.16711310.15672661279299
2.99-3.290.18221540.157826462800100
3.29-3.760.15281660.14492586275299
3.76-4.740.16521310.14512528265994
4.74-45.410.20831450.201226712816100

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