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- PDB-8aus: Small molecular stabilizer for ERalpha and 14-3-3 (1080297) -

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Basic information

Entry
Database: PDB / ID: 8aus
TitleSmall molecular stabilizer for ERalpha and 14-3-3 (1080297)
Components
  • 14-3-3 protein sigma
  • Estrogen receptor
KeywordsSTRUCTURAL PROTEIN / 14-3-3 / ERalpha / stabilization / covalent
Function / homology
Function and homology information


regulation of epithelial cell apoptotic process / antral ovarian follicle growth / G protein-coupled estrogen receptor activity / regulation of branching involved in prostate gland morphogenesis / RUNX1 regulates transcription of genes involved in WNT signaling / RUNX1 regulates estrogen receptor mediated transcription / regulation of toll-like receptor signaling pathway / nuclear estrogen receptor activity / prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis / regulation of epidermal cell division ...regulation of epithelial cell apoptotic process / antral ovarian follicle growth / G protein-coupled estrogen receptor activity / regulation of branching involved in prostate gland morphogenesis / RUNX1 regulates transcription of genes involved in WNT signaling / RUNX1 regulates estrogen receptor mediated transcription / regulation of toll-like receptor signaling pathway / nuclear estrogen receptor activity / prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis / regulation of epidermal cell division / protein kinase C inhibitor activity / epithelial cell proliferation involved in mammary gland duct elongation / positive regulation of epidermal cell differentiation / keratinocyte development / prostate epithelial cord elongation / keratinization / epithelial cell development / regulation of cell-cell adhesion / mammary gland branching involved in pregnancy / negative regulation of smooth muscle cell apoptotic process / uterus development / vagina development / cAMP/PKA signal transduction / TFIIB-class transcription factor binding / Regulation of localization of FOXO transcription factors / steroid hormone receptor signaling pathway / androgen metabolic process / keratinocyte proliferation / phosphoserine residue binding / mammary gland alveolus development / Activation of BAD and translocation to mitochondria / negative regulation of keratinocyte proliferation / cellular response to estrogen stimulus / estrogen response element binding / establishment of skin barrier / Mitochondrial unfolded protein response (UPRmt) / 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 / nuclear receptor-mediated steroid hormone signaling pathway / Nuclear signaling by ERBB4 / negative regulation of stem cell proliferation / SARS-CoV-1 targets host intracellular signalling and regulatory pathways / RNA polymerase II preinitiation complex assembly / RHO GTPases activate PKNs / negative regulation of canonical NF-kappaB signal transduction / positive regulation of protein localization / estrogen receptor signaling pathway / protein localization to chromatin / steroid binding / 14-3-3 protein binding / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / TBP-class protein binding / protein sequestering activity / nitric-oxide synthase regulator activity / positive regulation of cell adhesion / negative regulation of innate immune response / protein export from nucleus / negative regulation of miRNA transcription / release of cytochrome c from mitochondria / TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest / positive regulation of nitric-oxide synthase activity / ESR-mediated signaling / stem cell proliferation / transcription coregulator binding / positive regulation of protein export from nucleus / transcription corepressor binding / Translocation of SLC2A4 (GLUT4) to the plasma membrane / nuclear estrogen receptor binding / positive regulation of DNA-binding transcription factor activity / TP53 Regulates Metabolic Genes / negative regulation of protein kinase activity / stem cell differentiation / cellular response to estradiol stimulus / SUMOylation of intracellular receptors / negative regulation of DNA-binding transcription factor activity / transcription coactivator binding / euchromatin / beta-catenin binding / Nuclear Receptor transcription pathway / response to estrogen / nuclear receptor activity / Constitutive Signaling by Aberrant PI3K in Cancer / positive regulation of fibroblast proliferation / intrinsic apoptotic signaling pathway in response to DNA damage / male gonad development / Regulation of RUNX2 expression and activity / sequence-specific double-stranded DNA binding / positive regulation of nitric oxide biosynthetic process / Ovarian tumor domain proteases / protein localization / PIP3 activates AKT signaling / response to estradiol / regulation of protein localization / ATPase binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / positive regulation of cytosolic calcium ion concentration / positive regulation of cell growth / DNA-binding transcription activator activity, RNA polymerase II-specific / regulation of inflammatory response
Similarity search - Function
Estrogen receptor / Oestrogen-type nuclear receptor final C-terminal domain / : / Oestrogen receptor / Oestrogen-type nuclear receptor final C-terminal / 14-3-3 protein sigma / Estrogen receptor/oestrogen-related receptor / 14-3-3 proteins signature 2. / 14-3-3 protein, conserved site / 14-3-3 proteins signature 1. ...Estrogen receptor / Oestrogen-type nuclear receptor final C-terminal domain / : / Oestrogen receptor / Oestrogen-type nuclear receptor final C-terminal / 14-3-3 protein sigma / Estrogen receptor/oestrogen-related receptor / 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 / : / Nuclear hormone receptor / Nuclear hormones receptors DNA-binding region signature. / Zinc finger, nuclear hormone receptor-type / Double treble clef zinc finger, C4 type / Nuclear hormone receptors DNA-binding domain profile. / c4 zinc finger in nuclear hormone receptors / Nuclear hormone receptor, ligand-binding domain / Nuclear hormone receptor-like domain superfamily / Ligand-binding domain of nuclear hormone receptor / Nuclear receptor (NR) ligand-binding (LBD) domain profile. / Ligand binding domain of hormone receptors / Zinc finger, NHR/GATA-type
Similarity search - Domain/homology
Chem-O3F / Estrogen receptor / 14-3-3 protein sigma
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.4 Å
AuthorsVisser, E.J. / Vandenboorn, E.M.F. / Ottmann, C.
Funding support Netherlands, 1items
OrganizationGrant numberCountry
Netherlands Organisation for Scientific Research (NWO) Netherlands
CitationJournal: J.Am.Chem.Soc. / Year: 2023
Title: Structure-Based Optimization of Covalent, Small-Molecule Stabilizers of the 14-3-3 sigma /ER alpha Protein-Protein Interaction from Nonselective Fragments.
Authors: Konstantinidou, M. / Visser, E.J. / Vandenboorn, E. / Chen, S. / Jaishankar, P. / Overmans, M. / Dutta, S. / Neitz, R.J. / Renslo, A.R. / Ottmann, C. / Brunsveld, L. / Arkin, M.R.
History
DepositionAug 25, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 20, 2023Provider: repository / Type: Initial release
Revision 1.1Oct 4, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Oct 23, 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: Estrogen receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,6745
Polymers27,1572
Non-polymers5173
Water5,585310
1
A: 14-3-3 protein sigma
B: Estrogen receptor
hetero molecules

A: 14-3-3 protein sigma
B: Estrogen receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,34710
Polymers54,3134
Non-polymers1,0346
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_555x,-y,-z1
Buried area4330 Å2
ΔGint-45 kcal/mol
Surface area23920 Å2
MethodPISA
Unit cell
Length a, b, c (Å)81.879, 112.428, 62.485
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 Estrogen receptor / ER / ER-alpha / Estradiol receptor / Nuclear receptor subfamily 3 group A member 1


Mass: 613.596 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P03372
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-O3F / 2-chloranyl-~{N}-[[7-[4-[(4-chlorophenyl)amino]oxan-4-yl]carbonyl-7-azaspiro[3.5]nonan-2-yl]methyl]ethanamide


Mass: 468.417 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H31Cl2N3O3 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 310 / 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: 2.65 Å3/Da / Density % sol: 53.54 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 0.095 M HEPES (pH 7.1), PEG400 (24% (v/v)), 0.19 M CaCl2 and 5% (v/v) Glycerol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID30B / Wavelength: 0.976254 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Dec 3, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976254 Å / Relative weight: 1
ReflectionResolution: 1.4→45.48 Å / Num. obs: 54973 / % possible obs: 96.8 % / Redundancy: 2.5 % / CC1/2: 0.978 / Net I/σ(I): 8.5
Reflection shellResolution: 1.4→1.42 Å / Num. unique obs: 2686 / CC1/2: 0.978

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
PDB_EXTRACT3.27data extraction
DIALSdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4jC3

4jc3


Resolution: 1.4→45.48 Å / Cor.coef. Fo:Fc: 0.947 / Cor.coef. Fo:Fc free: 0.937 / SU B: 1.023 / SU ML: 0.042 / Cross valid method: THROUGHOUT / ESU R: 0.064 / ESU R Free: 0.065 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.21601 2784 5.1 %RANDOM
Rwork0.19378 ---
obs0.1949 52178 96.37 %-
Solvent computationIon probe radii: 0.7 Å / Shrinkage radii: 0.7 Å / VDW probe radii: 1.1 Å / Solvent model: MASK
Displacement parametersBiso mean: 13.729 Å2
Baniso -1Baniso -2Baniso -3
1--0 Å2-0 Å2-0 Å2
2--0.05 Å20 Å2
3----0.05 Å2
Refinement stepCycle: LAST / Resolution: 1.4→45.48 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1899 0 32 310 2241
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0171960
X-RAY DIFFRACTIONr_bond_other_d0.0010.0191857
X-RAY DIFFRACTIONr_angle_refined_deg1.5421.9022641
X-RAY DIFFRACTIONr_angle_other_deg1.2662.7014295
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.5765239
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.89722.642106
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.8815360
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.9871513
X-RAY DIFFRACTIONr_chiral_restr0.0940.2288
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.022194
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02420
X-RAY DIFFRACTIONr_mcbond_it0.941.189962
X-RAY DIFFRACTIONr_mcbond_other0.941.189961
X-RAY DIFFRACTIONr_mcangle_it1.4971.7811199
X-RAY DIFFRACTIONr_mcangle_other1.4961.7811200
X-RAY DIFFRACTIONr_scbond_it1.71.388998
X-RAY DIFFRACTIONr_scbond_other1.6991.388999
X-RAY DIFFRACTIONr_scangle_other2.5622.0051441
X-RAY DIFFRACTIONr_long_range_B_refined4.14815.6732450
X-RAY DIFFRACTIONr_long_range_B_other3.85314.9172357
LS refinement shellResolution: 1.4→1.436 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.254 198 -
Rwork0.225 3850 -
obs--96.66 %

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