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- PDB-8a65: Small molecule stabilizer (compound 3) for FOXO1 and 14-3-3 -

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Basic information

Entry
Database: PDB / ID: 8a65
TitleSmall molecule stabilizer (compound 3) 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 / regulation of neural precursor cell proliferation / neuronal stem cell population maintenance / response to fatty acid / negative regulation of stress-activated MAPK cascade ...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 / regulation of neural precursor cell proliferation / neuronal stem cell population maintenance / response to fatty acid / negative regulation of stress-activated MAPK cascade / Regulation of FOXO transcriptional activity by acetylation / negative regulation of cardiac muscle hypertrophy in response to stress / regulation of reactive oxygen species metabolic process / cellular response to cold / FOXO-mediated transcription of cell death genes / temperature homeostasis / protein acetylation / regulation of epidermal cell division / protein kinase C inhibitor activity / negative regulation of fat cell differentiation / positive regulation of epidermal cell differentiation / keratinocyte development / blood vessel development / keratinization / fat cell differentiation / intracellular glucose homeostasis / regulation of cell-cell adhesion / Constitutive Signaling by AKT1 E17K in Cancer / Regulation of gene expression in beta cells / Regulation of localization of FOXO transcription factors / keratinocyte proliferation / phosphoserine residue binding / negative regulation of keratinocyte proliferation / Activation of BAD and translocation to mitochondria / cellular response to nitric oxide / establishment of skin barrier / negative regulation of protein localization to plasma membrane / canonical Wnt signaling pathway / negative regulation of insulin secretion / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / positive regulation of autophagy / 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 / energy homeostasis / positive regulation of gluconeogenesis / negative regulation of innate immune response / protein sequestering activity / protein kinase A signaling / protein export from nucleus / cellular response to starvation / positive regulation of cell adhesion / release of cytochrome c from mitochondria / TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest / positive regulation of protein export from nucleus / stem cell proliferation / protein phosphatase 2A binding / Translocation of SLC2A4 (GLUT4) to the plasma membrane / promoter-specific chromatin binding / TP53 Regulates Metabolic Genes / negative regulation of protein kinase activity / MAPK6/MAPK4 signaling / negative regulation of canonical Wnt signaling pathway / chromatin DNA binding / DNA-binding transcription repressor activity, RNA polymerase II-specific / beta-catenin binding / cellular response to insulin stimulus / autophagy / intrinsic apoptotic signaling pathway in response to DNA damage / positive regulation of protein catabolic process / protein localization / insulin receptor signaling pathway / regulation of protein localization / cellular response to oxidative stress / gene expression / positive regulation of cell growth / DNA-binding transcription activator activity, RNA polymerase II-specific / Interleukin-4 and Interleukin-13 signaling / sequence-specific DNA binding / nucleic acid binding / regulation of cell cycle / DNA-binding transcription factor activity, RNA polymerase II-specific / cadherin binding / positive regulation of apoptotic process / DNA-binding transcription factor activity / RNA polymerase II cis-regulatory region sequence-specific DNA binding / negative regulation of DNA-templated transcription / DNA damage response / chromatin binding / ubiquitin protein ligase binding / chromatin / negative regulation of apoptotic process / regulation of transcription by RNA polymerase II / apoptotic process / protein kinase binding / 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 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
Similarity search - Domain/homology
Chem-L70 / 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

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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)28,2075
Polymers27,6792
Non-polymers5283
Water5,639313
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)56,41410
Polymers55,3584
Non-polymers1,0566
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_555x,-y,-z1
Buried area6140 Å2
ΔGint-62 kcal/mol
Surface area23480 Å2
MethodPISA
Unit cell
Length a, b, c (Å)81.879, 112.144, 62.632
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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: 1136.090 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-L70 / (3~{S})-1-[2-azanyl-3,5-bis(chloranyl)phenyl]carbonyl-~{N}-[2-[2-(dimethylamino)ethyldisulfanyl]ethyl]piperidine-3-carboxamide


Mass: 479.487 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H28Cl2N4O2S2 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 313 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.6 Å3/Da / Density % sol: 52.64 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 0.095 M HEPES pH 7.3, 0.19 M CaCl2, 5% glycerol, 25% 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 11, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.03322 Å / Relative weight: 1
ReflectionResolution: 1.6→45.47 Å / Num. obs: 518652 / % possible obs: 100 % / Redundancy: 13.5 % / CC1/2: 1 / Net I/σ(I): 55.7
Reflection shellResolution: 1.6→1.63 Å / Num. unique obs: 1881 / CC1/2: 0.997

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
PDB_EXTRACT3.27data extraction
HKL-2000data reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4JC3

4jc3


Resolution: 1.6→45.47 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.948 / SU B: 1.142 / SU ML: 0.042 / Cross valid method: THROUGHOUT / ESU R: 0.078 / ESU R Free: 0.078 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.1929 1954 5.1 %RANDOM
Rwork0.16668 ---
obs0.16803 36420 99.91 %-
Solvent computationIon probe radii: 0.9 Å / Shrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: MASK
Displacement parametersBiso mean: 18.161 Å2
Baniso -1Baniso -2Baniso -3
1-1.01 Å20 Å2-0 Å2
2---0.3 Å20 Å2
3----0.71 Å2
Refinement stepCycle: LAST / Resolution: 1.6→45.47 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1931 0 25 313 2269
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0171984
X-RAY DIFFRACTIONr_bond_other_d0.0010.021869
X-RAY DIFFRACTIONr_angle_refined_deg1.5881.9042673
X-RAY DIFFRACTIONr_angle_other_deg1.2982.7044325
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.0865242
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.14222.736106
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.80915364
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.3751514
X-RAY DIFFRACTIONr_chiral_restr0.0980.2289
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.022213
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02427
X-RAY DIFFRACTIONr_mcbond_it1.3681.553974
X-RAY DIFFRACTIONr_mcbond_other1.3671.548973
X-RAY DIFFRACTIONr_mcangle_it2.2672.3171214
X-RAY DIFFRACTIONr_mcangle_other2.2672.3221215
X-RAY DIFFRACTIONr_scbond_it2.4651.9021010
X-RAY DIFFRACTIONr_scbond_other2.4641.9051011
X-RAY DIFFRACTIONr_scangle_other3.6972.7561460
X-RAY DIFFRACTIONr_long_range_B_refined6.05820.9982523
X-RAY DIFFRACTIONr_long_range_B_other5.81820.2322439
LS refinement shellResolution: 1.6→1.642 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.191 140 -
Rwork0.161 2677 -
obs--99.86 %

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