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- PDB-8afn: Small molecule stabilizer (compound 1) for ERalpha and 14-3-3 -

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Basic information

Entry
Database: PDB / ID: 8afn
TitleSmall molecule stabilizer (compound 1) for ERalpha and 14-3-3
Components
  • 14-3-3 protein sigma
  • Estrogen receptor
KeywordsSTRUCTURAL PROTEIN / 14-3-3 / ERalpha / Stabilization
Function / homology
Function and homology information


regulation of epithelial cell apoptotic process / antral ovarian follicle growth / 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 / epithelial cell development / prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis / epithelial cell proliferation involved in mammary gland duct elongation ...regulation of epithelial cell apoptotic process / antral ovarian follicle growth / 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 / epithelial cell development / prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis / epithelial cell proliferation involved in mammary gland duct elongation / prostate epithelial cord elongation / regulation of epidermal cell division / protein kinase C inhibitor activity / positive regulation of epidermal cell differentiation / keratinocyte development / keratinization / mammary gland branching involved in pregnancy / regulation of cell-cell adhesion / negative regulation of smooth muscle cell apoptotic process / uterus development / vagina development / TFIIB-class transcription factor binding / steroid hormone receptor signaling pathway / androgen metabolic process / cAMP/PKA signal transduction / Regulation of localization of FOXO transcription factors / keratinocyte proliferation / phosphoserine residue binding / mammary gland alveolus development / cellular response to estrogen stimulus / estrogen response element binding / Activation of BAD and translocation to mitochondria / negative regulation of keratinocyte proliferation / Mitochondrial unfolded protein response (UPRmt) / establishment of skin barrier / nuclear receptor-mediated steroid hormone signaling pathway / 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 signaling by ERBB4 / negative regulation of stem cell proliferation / RNA polymerase II preinitiation complex assembly / SARS-CoV-1 targets host intracellular signalling and regulatory pathways / RHO GTPases activate PKNs / positive regulation of DNA-binding transcription factor activity / negative regulation of protein kinase activity / positive regulation of nitric-oxide synthase activity / estrogen receptor signaling pathway / positive regulation of protein localization / protein localization to chromatin / steroid binding / 14-3-3 protein binding / negative regulation of canonical NF-kappaB signal transduction / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / negative regulation of DNA-binding transcription factor activity / positive regulation of cell adhesion / negative regulation of miRNA transcription / protein sequestering activity / nitric-oxide synthase regulator activity / negative regulation of innate immune response / protein export from nucleus / ESR-mediated signaling / TBP-class protein binding / TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest / release of cytochrome c from mitochondria / transcription coregulator binding / positive regulation of protein export from nucleus / nuclear estrogen receptor binding / transcription corepressor binding / stem cell proliferation / Translocation of SLC2A4 (GLUT4) to the plasma membrane / TP53 Regulates Metabolic Genes / stem cell differentiation / cellular response to estradiol stimulus / SUMOylation of intracellular receptors / euchromatin / beta-catenin binding / Nuclear Receptor transcription pathway / response to estrogen / Regulation of RUNX2 expression and activity / transcription coactivator binding / nuclear receptor activity / Ovarian tumor domain proteases / positive regulation of fibroblast proliferation / male gonad development / intrinsic apoptotic signaling pathway in response to DNA damage / Constitutive Signaling by Aberrant PI3K in Cancer / positive regulation of nitric oxide biosynthetic process / sequence-specific double-stranded DNA binding / intracellular protein localization / response to estradiol / PIP3 activates AKT signaling / regulation of protein localization / positive regulation of cytosolic calcium ion concentration / ATPase binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / DNA-binding transcription activator activity, RNA polymerase II-specific / positive regulation of cell growth / regulation of inflammatory response / fibroblast proliferation
Similarity search - Function
14-3-3 domain / Delta-Endotoxin; domain 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 domain / Delta-Endotoxin; domain 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 / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-O6C / Estrogen receptor / 14-3-3 protein sigma
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.36 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
DepositionJul 18, 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 1.3Oct 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

Downloads & links

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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)27,6935
Polymers27,1572
Non-polymers5373
Water5,765320
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)55,38610
Polymers54,3134
Non-polymers1,0736
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_555x,-y,-z1
Unit cell
Length a, b, c (Å)81.742, 111.898, 62.555
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 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-O6C / 1-[2-(4-chloranylphenoxy)-2-methyl-propanoyl]-~{N}-[2-[2-(dimethylamino)ethyldisulfanyl]ethyl]piperidine-4-carboxamide


Mass: 488.107 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H34ClN3O3S2 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 320 / 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: 2.63 Å3/Da / Density % sol: 53.3 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 0.095 M HEPES pH 7.1, 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: 1.033 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 7, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.033 Å / Relative weight: 1
ReflectionResolution: 1.36→66.01 Å / Num. obs: 113349 / % possible obs: 96.3 % / Redundancy: 1.9 % / CC1/2: 1 / Net I/σ(I): 26.6
Reflection shellResolution: 1.36→1.38 Å / Num. unique obs: 2234 / CC1/2: 0.68

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Processing

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

4jc3


Resolution: 1.36→45.4 Å / SU ML: 0.11 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 19.98 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1848 5660 4.99 %
Rwork0.1732 107684 -
obs0.1738 113344 95.15 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 90.37 Å2 / Biso mean: 21.6922 Å2 / Biso min: 8.54 Å2
Refinement stepCycle: final / Resolution: 1.36→45.4 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1882 0 52 320 2254
Biso mean--23.75 29.78 -
Num. residues----241
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 30

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.36-1.380.31791100.30722306241661
1.38-1.390.2626920.29142620271267
1.39-1.410.28791330.27662750288374
1.41-1.430.30471720.27183023319581
1.43-1.450.23021690.24423225339485
1.45-1.460.22291270.23223481360892
1.47-1.490.21412010.20833653385496
1.49-1.510.222110.19643732394399
1.51-1.530.20471900.191937603950100
1.53-1.560.19861670.182238103977100
1.56-1.580.19571950.177237783973100
1.58-1.610.2062060.179837643970100
1.61-1.640.19311690.176238083977100
1.64-1.680.19282060.178737043910100
1.68-1.710.18152140.180137633977100
1.71-1.750.19861920.183137953987100
1.75-1.80.20961890.181337933982100
1.8-1.850.19471800.170737673947100
1.85-1.90.18162210.177437673988100
1.9-1.960.18841980.168337643962100
1.96-2.030.20361780.175138003978100
2.03-2.110.19611920.15937763968100
2.11-2.210.17362450.154837313976100
2.21-2.330.15442110.15137934004100
2.33-2.470.17592390.155937183957100
2.47-2.660.17382070.15937773984100
2.66-2.930.17882160.168237413957100
2.93-3.350.19022200.172337253945100
3.35-4.220.15672190.155337683987100
4.22-45.40.18981910.182737923983100

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