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- PDB-9i6s: 14-3-3sigma binding to the ERa peptide and compound 28 -

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Basic information

Entry
Database: PDB / ID: 9i6s
Title14-3-3sigma binding to the ERa peptide and compound 28
Components
  • 14-3-3 protein sigma
  • Estrogen receptor
KeywordsPEPTIDE BINDING PROTEIN / 14-3-3 / protein-protein interactions / 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 / steroid hormone receptor signaling pathway / prostate epithelial cord 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 / steroid hormone receptor signaling pathway / prostate epithelial cord elongation / epithelial cell proliferation involved in mammary gland duct elongation / regulation of epidermal cell division / protein kinase C inhibitor activity / prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis / positive regulation of epidermal cell differentiation / keratinocyte development / keratinization / mammary gland branching involved in pregnancy / regulation of cell-cell adhesion / uterus development / negative regulation of smooth muscle cell apoptotic process / vagina development / TFIIB-class transcription factor binding / androgen metabolic process / cAMP/PKA signal transduction / Regulation of localization of FOXO transcription factors / keratinocyte proliferation / mammary gland alveolus development / cellular response to estrogen stimulus / estrogen response element binding / Activation of BAD and translocation to mitochondria / phosphoserine residue binding / negative regulation of keratinocyte proliferation / establishment of skin barrier / Mitochondrial unfolded protein response (UPRmt) / 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 protein kinase activity / negative regulation of stem cell proliferation / RNA polymerase II preinitiation complex assembly / RHO GTPases activate PKNs / SARS-CoV-1 targets host intracellular signalling and regulatory pathways / positive regulation of nitric-oxide synthase activity / 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 / negative regulation of canonical NF-kappaB signal transduction / positive regulation of cell adhesion / protein sequestering activity / negative regulation of innate immune response / ESR-mediated signaling / negative regulation of miRNA transcription / protein export from nucleus / TBP-class protein binding / TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest / release of cytochrome c from mitochondria / positive regulation of protein export from nucleus / nitric-oxide synthase regulator activity / nuclear estrogen receptor binding / stem cell proliferation / transcription corepressor binding / transcription coregulator binding / TP53 Regulates Metabolic Genes / Translocation of SLC2A4 (GLUT4) to the plasma membrane / stem cell differentiation / SUMOylation of intracellular receptors / cellular response to estradiol stimulus / euchromatin / beta-catenin binding / Nuclear Receptor transcription pathway / response to estrogen / transcription coactivator binding / male gonad development / nuclear receptor activity / positive regulation of fibroblast proliferation / intrinsic apoptotic signaling pathway in response to DNA damage / Constitutive Signaling by Aberrant PI3K in Cancer / sequence-specific double-stranded DNA binding / positive regulation of nitric oxide biosynthetic process / Regulation of RUNX2 expression and activity / Ovarian tumor domain proteases / 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 / positive regulation of cell growth / regulation of inflammatory response / DNA-binding transcription activator activity, RNA polymerase II-specific / fibroblast proliferation
Similarity search - Function
Oestrogen-type nuclear receptor final C-terminal domain / Oestrogen-type nuclear receptor final C-terminal / Estrogen receptor / : / Oestrogen receptor / 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. ...Oestrogen-type nuclear receptor final C-terminal domain / Oestrogen-type nuclear receptor final C-terminal / Estrogen receptor / : / Oestrogen receptor / 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
: / Estrogen receptor / 14-3-3 protein sigma
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.3 Å
AuthorsPennings, M.A.M. / Arkin, M.R.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM147696 United States
CitationJournal: Nat Commun / Year: 2025
Title: Scaffold-hopping for molecular glues targeting the 14-3-3/ER alpha complex.
Authors: Konstantinidou, M. / Zingiridis, M. / Pennings, M.A.M. / Fragkiadakis, M. / Virta, J.M. / Revalde, J.L. / Visser, E.J. / Ottmann, C. / Brunsveld, L. / Neochoritis, C.G. / Arkin, M.R.
History
DepositionJan 31, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 30, 2025Provider: repository / Type: Initial release

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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)27,7166
Polymers27,1572
Non-polymers5604
Water5,026279
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)55,43212
Polymers54,3134
Non-polymers1,1198
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_555x,-y,-z1
Buried area4430 Å2
ΔGint-66 kcal/mol
Surface area23980 Å2
MethodPISA
Unit cell
Length a, b, c (Å)82.960, 113.103, 62.965
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11A-302-

CA

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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-A1I0P / 2-chloranyl-~{N}-[4-[3-[(2-chloranyl-6-methyl-phenyl)amino]-6-methyl-imidazo[1,2-a]pyridin-2-yl]phenyl]ethanamide


Mass: 439.337 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H20Cl2N4O / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Ca
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 279 / 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: 2.72 Å3/Da / Density % sol: 54.77 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 0.095 M HEPES pH=7.1-7.7 0.19 M CaCl2 5% glycerol 24-29% PEG400

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-2 / Wavelength: 0.873128 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Jun 14, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.873128 Å / Relative weight: 1
ReflectionResolution: 1.3→66.89 Å / Num. obs: 72898 / % possible obs: 100 % / Redundancy: 11.3 % / CC1/2: 0.999 / Net I/σ(I): 16.8
Reflection shellResolution: 1.3→1.32 Å / Mean I/σ(I) obs: 2.1 / Num. unique obs: 3565 / CC1/2: 0.726

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Processing

Software
NameClassification
PDB-REDOrefinement
autoPROCdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.3→45.89 Å / Cor.coef. Fo:Fc: 0.977 / Cor.coef. Fo:Fc free: 0.969 / SU B: 2.145 / SU ML: 0.038 / Cross valid method: THROUGHOUT / ESU R: 0.043 / ESU R Free: 0.043 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.18217 3678 5 %RANDOM
Rwork0.14996 ---
obs0.15162 69191 99.93 %-
Solvent computationIon probe radii: 0.9 Å / Shrinkage radii: 0.9 Å / VDW probe radii: 1.6 Å / Solvent model: MASK
Displacement parametersBiso mean: 20.39 Å2
Baniso -1Baniso -2Baniso -3
1--0.89 Å2-0 Å2-0 Å2
2--3.07 Å20 Å2
3----2.18 Å2
Refinement stepCycle: LAST / Resolution: 1.3→45.89 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1899 0 32 279 2210
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0180.0162004
X-RAY DIFFRACTIONr_bond_other_d0.0010.0161887
X-RAY DIFFRACTIONr_angle_refined_deg1.4991.8242714
X-RAY DIFFRACTIONr_angle_other_deg0.5771.5674366
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.6745.241270
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.19417.56
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.30610374
X-RAY DIFFRACTIONr_chiral_restr0.0790.2296
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.022362
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02435
X-RAY DIFFRACTIONr_mcbond_it6.9571.7980
X-RAY DIFFRACTIONr_mcbond_other6.9551.7980
X-RAY DIFFRACTIONr_mcangle_it9.043.0791226
X-RAY DIFFRACTIONr_mcangle_other9.0383.0791227
X-RAY DIFFRACTIONr_scbond_it11.6422.1321024
X-RAY DIFFRACTIONr_scbond_other11.642.1311024
X-RAY DIFFRACTIONr_scangle_other15.2843.7361480
X-RAY DIFFRACTIONr_long_range_B_refined17.36922.272434
X-RAY DIFFRACTIONr_long_range_B_other16.57220.532360
X-RAY DIFFRACTIONr_rigid_bond_restr6.5733891
LS refinement shellResolution: 1.3→1.334 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.242 294 -
Rwork0.248 5030 -
obs--99.87 %

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