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- PDB-8aze: Small molecule stabilizer for ERalpha and 14-3-3 (1075306) -

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Basic information

Entry
Database: PDB / ID: 8aze
TitleSmall molecule stabilizer for ERalpha and 14-3-3 (1075306)
Components
  • 14-3-3 protein sigma
  • ERalpha peptide
KeywordsSTRUCTURAL PROTEIN / 14-3-3 / ERalpha / stabilizer
Function / homology
Function and homology information


regulation of epidermal cell division / protein kinase C inhibitor activity / positive regulation of epidermal cell differentiation / keratinocyte development / keratinization / Regulation of localization of FOXO transcription factors / keratinocyte proliferation / phosphoserine residue binding / Activation of BAD and translocation to mitochondria / negative regulation of keratinocyte proliferation ...regulation of epidermal cell division / protein kinase C inhibitor activity / positive regulation of epidermal cell differentiation / keratinocyte development / keratinization / Regulation of localization of FOXO transcription factors / keratinocyte proliferation / phosphoserine residue binding / Activation of BAD and translocation to mitochondria / negative regulation of keratinocyte proliferation / establishment of skin barrier / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / protein kinase A signaling / negative regulation of stem cell proliferation / SARS-CoV-1 targets host intracellular signalling and regulatory pathways / RHO GTPases activate PKNs / protein export from nucleus / negative regulation of innate immune response / protein sequestering activity / TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest / release of cytochrome c from mitochondria / positive regulation of protein export from nucleus / stem cell proliferation / Translocation of SLC2A4 (GLUT4) to the plasma membrane / TP53 Regulates Metabolic Genes / negative regulation of protein kinase activity / negative regulation of cysteine-type endopeptidase activity involved in apoptotic process / intrinsic apoptotic signaling pathway in response to DNA damage / positive regulation of cell growth / regulation of cell cycle / cadherin binding / protein kinase binding / negative regulation of transcription by RNA polymerase II / signal transduction / extracellular space / extracellular exosome / identical protein binding / nucleus / cytosol / cytoplasm
Similarity search - Function
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
Similarity search - Domain/homology
Chem-O5I / 14-3-3 protein sigma
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 Å
AuthorsKonstantinidou, M. / Visser, E.J. / Vandenboorn, E.M.F. / Sheng, C. / Jaishankar, P. / Overmans, M.J.A.M. / Dutta, S. / Neitz, J. / Renslo, A. / Ottmann, C. ...Konstantinidou, M. / Visser, E.J. / Vandenboorn, E.M.F. / Sheng, C. / Jaishankar, P. / Overmans, M.J.A.M. / Dutta, S. / Neitz, J. / Renslo, A. / Ottmann, C. / Brunsveld, L. / Arkin, M.
Funding support Netherlands, 1items
OrganizationGrant numberCountry
Netherlands Organisation for Scientific Research (NWO)024.001.035 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
DepositionSep 6, 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: ERalpha peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,6426
Polymers27,1572
Non-polymers4854
Water5,224290
1
A: 14-3-3 protein sigma
B: ERalpha peptide
hetero molecules

A: 14-3-3 protein sigma
B: ERalpha peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,28412
Polymers54,3134
Non-polymers9718
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_555x,-y,-z1
Buried area4390 Å2
ΔGint-45 kcal/mol
Surface area23570 Å2
Unit cell
Length a, b, c (Å)81.846, 111.849, 62.305
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-

MG

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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 ERalpha peptide


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


Mass: 24.305 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-O5I / 2-chloranyl-~{N}-[[1-[1-[(4-chlorophenyl)amino]cyclopentyl]carbonylpiperidin-4-yl]methyl]ethanamide


Mass: 412.353 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H27Cl2N3O2 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 290 / 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: 2.62 Å3/Da / Density % sol: 53.13 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 35% (v/v) 2-Ethoxyethanol, 100 mM Imidazole/ Hydrochloric acid pH 8.0, 50 mM Calcium acetate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: MASSIF-1 / Wavelength: 1.0332 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Nov 26, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0332 Å / Relative weight: 1
ReflectionResolution: 1.6→45.32 Å / Num. obs: 37965 / % possible obs: 99.71 % / Redundancy: 4.7 % / CC1/2: 0.997 / Net I/σ(I): 17.6
Reflection shellResolution: 1.6→1.657 Å / Num. unique obs: 3725 / CC1/2: 0.968

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Processing

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

4jc3


Resolution: 1.6→45.32 Å / Cor.coef. Fo:Fc: 0.958 / Cor.coef. Fo:Fc free: 0.939 / SU B: 1.324 / SU ML: 0.048 / Cross valid method: THROUGHOUT / ESU R: 0.078 / ESU R Free: 0.081 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2013 1852 4.9 %RANDOM
Rwork0.16706 ---
obs0.16878 36144 99.63 %-
Solvent computationIon probe radii: 0.7 Å / Shrinkage radii: 0.7 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 17.974 Å2
Baniso -1Baniso -2Baniso -3
1-0.35 Å20 Å2-0 Å2
2---0.1 Å20 Å2
3----0.25 Å2
Refinement stepCycle: LAST / Resolution: 1.6→45.32 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1898 0 29 290 2217
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0171954
X-RAY DIFFRACTIONr_bond_other_d0.0010.0191853
X-RAY DIFFRACTIONr_angle_refined_deg1.331.8992630
X-RAY DIFFRACTIONr_angle_other_deg1.2472.7034285
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.8675239
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.52722.642106
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.89915360
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.9531513
X-RAY DIFFRACTIONr_chiral_restr0.0820.2287
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.022190
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02420
X-RAY DIFFRACTIONr_mcbond_it8.0731.48962
X-RAY DIFFRACTIONr_mcbond_other8.0731.479961
X-RAY DIFFRACTIONr_mcangle_it9.4152.1951199
X-RAY DIFFRACTIONr_mcangle_other9.4132.1951200
X-RAY DIFFRACTIONr_scbond_it11.2971.929992
X-RAY DIFFRACTIONr_scbond_other11.2911.929993
X-RAY DIFFRACTIONr_scangle_other11.6962.6171432
X-RAY DIFFRACTIONr_long_range_B_refined12.23218.6172438
X-RAY DIFFRACTIONr_long_range_B_other12.3117.9292356
LS refinement shellResolution: 1.6→1.641 Å
RfactorNum. reflection% reflection
Rfree0.263 110 -
Rwork0.173 2610 -
obs--97.95 %

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