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- PDB-6ygj: small-molecule stabilizer of 14-3-3 and the Carbohydrate Response... -

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Basic information

Entry
Database: PDB / ID: 6ygj
Titlesmall-molecule stabilizer of 14-3-3 and the Carbohydrate Response Element Binding Protein (ChREBP) protein-protein interaction
Components
  • (14-3-3 protein beta/alpha) x 2
  • Carbohydrate-responsive element-binding protein
KeywordsSTRUCTURAL PROTEIN / 14-3-3 / Stabilizer / protein-protein interaction / ChREBP / small molecule
Function / homology
Function and homology information


carbohydrate response element binding / : / glucose mediated signaling pathway / PKA-mediated phosphorylation of key metabolic factors / AMPK inhibits chREBP transcriptional activation activity / PP2A-mediated dephosphorylation of key metabolic factors / positive regulation of transcription from RNA polymerase II promoter by glucose / cytoplasmic sequestering of protein / Tristetraprolin (TTP, ZFP36) binds and destabilizes mRNA / Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA ...carbohydrate response element binding / : / glucose mediated signaling pathway / PKA-mediated phosphorylation of key metabolic factors / AMPK inhibits chREBP transcriptional activation activity / PP2A-mediated dephosphorylation of key metabolic factors / positive regulation of transcription from RNA polymerase II promoter by glucose / cytoplasmic sequestering of protein / Tristetraprolin (TTP, ZFP36) binds and destabilizes mRNA / Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA / ChREBP activates metabolic gene expression / positive regulation of fatty acid biosynthetic process / MTOR signalling / ARMS-mediated activation / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / Rap1 signalling / negative regulation of oxidative phosphorylation / positive regulation of catalytic activity / Signaling by Hippo / triglyceride homeostasis / vacuolar membrane / lipid biosynthetic process / negative regulation of G protein-coupled receptor signaling pathway / DNA-binding transcription activator activity / Frs2-mediated activation / negative regulation of peptidyl-serine phosphorylation / protein kinase inhibitor activity / mTORC1-mediated signalling / Regulation of localization of FOXO transcription factors / phosphoserine residue binding / Activation of BAD and translocation to mitochondria / anatomical structure morphogenesis / fatty acid homeostasis / protein targeting / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / positive regulation of lipid biosynthetic process / SARS-CoV-1 targets host intracellular signalling and regulatory pathways / RHO GTPases activate PKNs / energy homeostasis / positive regulation of glycolytic process / Translocation of SLC2A4 (GLUT4) to the plasma membrane / TP53 Regulates Metabolic Genes / phosphoprotein binding / RAF activation / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / DNA-binding transcription repressor activity, RNA polymerase II-specific / histone deacetylase binding / Negative regulation of MAPK pathway / Signaling by RAF1 mutants / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants / Signaling by BRAF and RAF1 fusions / protein localization / melanosome / glucose homeostasis / DNA-binding transcription activator activity, RNA polymerase II-specific / DNA-binding transcription factor binding / RNA polymerase II-specific DNA-binding transcription factor binding / transcription regulator complex / DNA-binding transcription factor activity, RNA polymerase II-specific / cadherin binding / protein heterodimerization activity / DNA-binding transcription factor activity / RNA polymerase II cis-regulatory region sequence-specific DNA binding / protein domain specific binding / focal adhesion / negative regulation of DNA-templated transcription / positive regulation of cell population proliferation / regulation of DNA-templated transcription / chromatin / regulation of transcription by RNA polymerase II / positive regulation of DNA-templated transcription / perinuclear region of cytoplasm / enzyme binding / signal transduction / positive regulation of transcription by RNA polymerase II / DNA binding / extracellular exosome / nucleoplasm / identical protein binding / membrane / nucleus / cytosol / cytoplasm
Similarity search - Function
Helix-loop-helix DNA-binding domain / 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 / helix loop helix domain ...Helix-loop-helix DNA-binding domain / 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 / helix loop helix domain / Myc-type, basic helix-loop-helix (bHLH) domain / Myc-type, basic helix-loop-helix (bHLH) domain profile. / Helix-loop-helix DNA-binding domain superfamily
Similarity search - Domain/homology
Chem-OQE / 14-3-3 protein beta/alpha / Carbohydrate-responsive element-binding protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.07 Å
AuthorsOttmann, C. / Visser, E.J.
Funding support Netherlands, Germany, 4items
OrganizationGrant numberCountry
Netherlands Organisation for Scientific Research (NWO)024.001.035 Netherlands
Netherlands Organisation for Scientific Research (NWO)016.150.366 Netherlands
Netherlands Organisation for Scientific Research (NWO)711.018.003 Netherlands
German Research Foundation (DFG)CRC1093 Germany
CitationJournal: Nat Commun / Year: 2020
Title: Structure-based evolution of a promiscuous inhibitor to a selective stabilizer of protein-protein interactions.
Authors: Sijbesma, E. / Visser, E. / Plitzko, K. / Thiel, P. / Milroy, L.G. / Kaiser, M. / Brunsveld, L. / Ottmann, C.
History
DepositionMar 27, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 16, 2020Provider: repository / Type: Initial release
Revision 1.1Jan 24, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: 14-3-3 protein beta/alpha
B: Carbohydrate-responsive element-binding protein
F: 14-3-3 protein beta/alpha
I: Carbohydrate-responsive element-binding protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)59,1376
Polymers58,4664
Non-polymers6712
Water64936
1
A: 14-3-3 protein beta/alpha
B: Carbohydrate-responsive element-binding protein
hetero molecules

F: 14-3-3 protein beta/alpha
I: Carbohydrate-responsive element-binding protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)59,1376
Polymers58,4664
Non-polymers6712
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_565x,y+1,z1
Unit cell
Length a, b, c (Å)98.787, 76.686, 90.289
Angle α, β, γ (deg.)90.000, 119.220, 90.000
Int Tables number5
Space group name H-MC121

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Components

#1: Protein 14-3-3 protein beta/alpha / Protein 1054 / Protein kinase C inhibitor protein 1 / KCIP-1


Mass: 26348.631 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: YWHAB / Production host: Escherichia coli (E. coli) / References: UniProt: P31946
#2: Protein/peptide Carbohydrate-responsive element-binding protein / ChREBP / Class D basic helix-loop-helix protein 14 / bHLHd14 / MLX interactor / MLX-interacting ...ChREBP / Class D basic helix-loop-helix protein 14 / bHLHd14 / MLX interactor / MLX-interacting protein-like / WS basic-helix-loop-helix leucine zipper protein / WS-bHLH / Williams-Beuren syndrome chromosomal region 14 protein


Mass: 2768.206 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: Q9NP71
#3: Protein 14-3-3 protein beta/alpha / Protein 1054 / Protein kinase C inhibitor protein 1 / KCIP-1


Mass: 26580.928 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: YWHAB / Production host: Escherichia coli (E. coli) / References: UniProt: P31946
#4: Chemical ChemComp-OQE / [2-[2-oxidanylidene-2-(2-phenylethylamino)ethoxy]phenyl]phosphonic acid


Mass: 335.292 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H18NO5P / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 36 / 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: 2.55 Å3/Da / Density % sol: 51.81 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop
Details: 0.1M HEPES (pH 7.1), 30% MPD, 1% PEG 4000, 0.1 M Ni(II)Cl 6H2O

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: PETRA III, DESY / Beamline: P11 / Wavelength: 1.0332 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: May 18, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0332 Å / Relative weight: 1
ReflectionResolution: 2.07→57.3 Å / Num. obs: 35961 / % possible obs: 99.94 % / Redundancy: 50.51 % / CC1/2: 0.999 / Net I/σ(I): 14.8
Reflection shellResolution: 2.07→2.14 Å / Num. unique obs: 3582 / CC1/2: 0.973

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
PDB_EXTRACT3.25data extraction
DIALSdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5F74

5f74


Resolution: 2.07→57.3 Å / SU ML: 0.33 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 31.84
RfactorNum. reflection% reflection
Rfree0.2771 1778 4.95 %
Rwork0.2209 --
obs0.2237 35948 99.86 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 285.45 Å2 / Biso mean: 77.4586 Å2 / Biso min: 34.51 Å2
Refinement stepCycle: final / Resolution: 2.07→57.3 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4032 0 78 36 4146
Biso mean--76.39 57.42 -
Num. residues----495
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 13

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.07-2.130.3651310.32573270499
2.13-2.190.33991450.291626112756100
2.19-2.260.34751440.272526122756100
2.26-2.340.33711450.268525942739100
2.34-2.430.31941160.255626482764100
2.43-2.540.32451320.262626172749100
2.54-2.680.33141200.257726432763100
2.68-2.850.2881710.246326182789100
2.85-3.060.33331260.253726122738100
3.07-3.370.32551530.245426222775100
3.37-3.860.29591350.211926452780100
3.86-4.860.23311440.183526462790100
4.87-57.30.23791160.209327292845100

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