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- PDB-8aqe: Small molecular stabilizer for ERalpha and 14-3-3 (1080295) -

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Basic information

Entry
Database: PDB / ID: 8aqe
TitleSmall molecular stabilizer for ERalpha and 14-3-3 (1080295)
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 / prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis / regulation of branching involved in prostate gland morphogenesis / prostate epithelial cord elongation / RUNX1 regulates transcription of genes involved in WNT signaling / RUNX1 regulates estrogen receptor mediated transcription / regulation of toll-like receptor signaling pathway / regulation of epidermal cell division ...regulation of epithelial cell apoptotic process / antral ovarian follicle growth / G protein-coupled estrogen receptor activity / prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis / regulation of branching involved in prostate gland morphogenesis / prostate epithelial cord elongation / RUNX1 regulates transcription of genes involved in WNT signaling / RUNX1 regulates estrogen receptor mediated transcription / regulation of toll-like receptor signaling pathway / regulation of epidermal cell division / protein kinase C inhibitor activity / nuclear estrogen receptor activity / positive regulation of epidermal cell differentiation / epithelial cell proliferation involved in mammary gland duct elongation / keratinocyte development / epithelial cell development / keratinization / vagina development / regulation of cell-cell adhesion / mammary gland branching involved in pregnancy / negative regulation of smooth muscle cell apoptotic process / uterus development / TFIIB-class transcription factor binding / androgen metabolic process / Regulation of localization of FOXO transcription factors / steroid hormone receptor signaling pathway / keratinocyte proliferation / phosphoserine residue binding / negative regulation of keratinocyte proliferation / Activation of BAD and translocation to mitochondria / mammary gland alveolus development / cellular response to estrogen stimulus / establishment of skin barrier / negative regulation of protein localization to plasma membrane / estrogen response element binding / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / nuclear receptor-mediated steroid hormone signaling pathway / negative regulation of stem cell proliferation / negative regulation of canonical NF-kappaB signal transduction / SARS-CoV-1 targets host intracellular signalling and regulatory pathways / Nuclear signaling by ERBB4 / positive regulation of protein localization / RNA polymerase II preinitiation complex assembly / RHO GTPases activate PKNs / 14-3-3 protein binding / negative regulation of innate immune response / protein localization to chromatin / estrogen receptor signaling pathway / protein sequestering activity / protein kinase A signaling / steroid binding / nitric-oxide synthase regulator activity / TBP-class protein binding / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / protein export from nucleus / positive regulation of cell adhesion / ESR-mediated signaling / release of cytochrome c from mitochondria / TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest / transcription corepressor binding / negative regulation of miRNA transcription / positive regulation of protein export from nucleus / positive regulation of nitric-oxide synthase activity / stem cell proliferation / cellular response to estradiol stimulus / transcription coregulator binding / Translocation of SLC2A4 (GLUT4) to the plasma membrane / stem cell differentiation / nuclear estrogen receptor binding / TP53 Regulates Metabolic Genes / positive regulation of DNA-binding transcription factor activity / negative regulation of protein kinase activity / SUMOylation of intracellular receptors / euchromatin / negative regulation of DNA-binding transcription factor activity / transcription coactivator binding / beta-catenin binding / Nuclear Receptor transcription pathway / response to estrogen / intrinsic apoptotic signaling pathway in response to DNA damage / Constitutive Signaling by Aberrant PI3K in Cancer / male gonad development / nuclear receptor activity / Regulation of RUNX2 expression and activity / positive regulation of fibroblast proliferation / sequence-specific double-stranded DNA binding / positive regulation of nitric oxide biosynthetic process / protein localization / Ovarian tumor domain proteases / PIP3 activates AKT signaling / response to estradiol / regulation of protein localization / phospholipase C-activating G protein-coupled receptor signaling pathway / ATPase binding / regulation of inflammatory response / positive regulation of cytosolic calcium ion concentration / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / fibroblast proliferation / positive regulation of cell growth
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 / Zinc finger, C4 type (two domains) / 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-NE9 / Estrogen receptor / 14-3-3 protein sigma
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 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 12, 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

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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)27,6605
Polymers27,1572
Non-polymers5033
Water5,134285
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)55,31910
Polymers54,3134
Non-polymers1,0066
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_555x,-y,-z1
Unit cell
Length a, b, c (Å)81.941, 112.391, 62.426
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-NE9 / 2-chloranyl-N-[7-[4-[(4-chlorophenyl)amino]oxan-4-yl]carbonyl-7-azaspiro[3.5]nonan-2-yl]ethanamide


Mass: 454.390 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H29Cl2N3O3 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 285 / 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: 2.65 Å3/Da / Density % sol: 53.52 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 0.095 M HEPES (pH 7.3), 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: 0.97625 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Dec 3, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97625 Å / Relative weight: 1
ReflectionResolution: 1.6→34.09 Å / Num. obs: 31647 / % possible obs: 83 % / Redundancy: 3.5 % / CC1/2: 0.989 / Net I/σ(I): 14.9
Reflection shellResolution: 1.6→1.63 Å / Num. unique obs: 1677 / CC1/2: 0.975

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
DIALSdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4JC3

4jc3


Resolution: 1.6→34.09 Å / Cor.coef. Fo:Fc: 0.939 / Cor.coef. Fo:Fc free: 0.912 / SU B: 1.699 / SU ML: 0.061 / Cross valid method: THROUGHOUT / ESU R: 0.111 / ESU R Free: 0.113 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.24032 1634 5.2 %RANDOM
Rwork0.19788 ---
obs0.20001 29994 82.36 %-
Solvent computationIon probe radii: 0.7 Å / Shrinkage radii: 0.7 Å / VDW probe radii: 1 Å / Solvent model: MASK
Displacement parametersBiso mean: 14.216 Å2
Baniso -1Baniso -2Baniso -3
1-1.07 Å20 Å2-0 Å2
2---0.38 Å20 Å2
3----0.7 Å2
Refinement stepCycle: LAST / Resolution: 1.6→34.09 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1899 0 31 285 2215
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0171959
X-RAY DIFFRACTIONr_bond_other_d0.0010.0191855
X-RAY DIFFRACTIONr_angle_refined_deg1.2161.92640
X-RAY DIFFRACTIONr_angle_other_deg1.1622.7024290
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.5365239
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.97722.642106
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.18515360
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.0421513
X-RAY DIFFRACTIONr_chiral_restr0.0720.2288
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.022190
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02420
X-RAY DIFFRACTIONr_mcbond_it2.0131.159962
X-RAY DIFFRACTIONr_mcbond_other2.0121.159961
X-RAY DIFFRACTIONr_mcangle_it2.7731.7331199
X-RAY DIFFRACTIONr_mcangle_other2.7731.7331200
X-RAY DIFFRACTIONr_scbond_it3.3731.5997
X-RAY DIFFRACTIONr_scbond_other3.3711.502998
X-RAY DIFFRACTIONr_scangle_other4.7022.1291440
X-RAY DIFFRACTIONr_long_range_B_refined5.77715.8462403
X-RAY DIFFRACTIONr_long_range_B_other5.67515.3412344
LS refinement shellResolution: 1.6→1.642 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.248 110 -
Rwork0.198 2303 -
obs--85.36 %

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