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- PDB-9ew6: Binary structure of 14-3-3s and BRAF phosphopeptide (pS365) -

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Basic information

Entry
Database: PDB / ID: 9ew6
TitleBinary structure of 14-3-3s and BRAF phosphopeptide (pS365)
Components
  • 14-3-3 protein sigma
  • Serine/threonine-protein kinase B-raf
KeywordsPEPTIDE BINDING PROTEIN / 14-3-3 protein / protein-protein interaction
Function / homology
Function and homology information


CD4-positive, alpha-beta T cell differentiation / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / negative regulation of synaptic vesicle exocytosis / Signalling to p38 via RIT and RIN / myeloid progenitor cell differentiation / head morphogenesis / ARMS-mediated activation / endothelial cell apoptotic process / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling ...CD4-positive, alpha-beta T cell differentiation / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / negative regulation of synaptic vesicle exocytosis / Signalling to p38 via RIT and RIN / myeloid progenitor cell differentiation / head morphogenesis / ARMS-mediated activation / endothelial cell apoptotic process / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / negative regulation of fibroblast migration / positive regulation of D-glucose transmembrane transport / establishment of protein localization to membrane / positive regulation of axonogenesis / regulation of T cell differentiation / mitogen-activated protein kinase kinase binding / Negative feedback regulation of MAPK pathway / Frs2-mediated activation / regulation of epidermal cell division / protein kinase C inhibitor activity / positive regulation of epidermal cell differentiation / keratinocyte development / positive regulation of axon regeneration / keratinization / stress fiber assembly / regulation of cell-cell adhesion / face development / MAP kinase kinase activity / synaptic vesicle exocytosis / thyroid gland development / cAMP/PKA signal transduction / Regulation of localization of FOXO transcription factors / somatic stem cell population maintenance / keratinocyte proliferation / phosphoserine residue binding / MAP kinase kinase kinase activity / Activation of BAD and translocation to mitochondria / negative regulation of keratinocyte proliferation / establishment of skin barrier / negative regulation of protein localization to plasma membrane / postsynaptic modulation of chemical synaptic transmission / negative regulation of endothelial cell apoptotic process / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / negative regulation of stem cell proliferation / response to cAMP / SARS-CoV-1 targets host intracellular signalling and regulatory pathways / RHO GTPases activate PKNs / positive regulation of peptidyl-serine phosphorylation / positive regulation of protein localization / positive regulation of stress fiber assembly / positive regulation of substrate adhesion-dependent cell spreading / ERK1 and ERK2 cascade / positive regulation of cell adhesion / substrate adhesion-dependent cell spreading / protein sequestering activity / cellular response to calcium ion / negative regulation of innate immune response / protein export from nucleus / release of cytochrome c from mitochondria / TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest / thymus development / positive regulation of protein export from nucleus / animal organ morphogenesis / negative regulation of protein kinase activity / stem cell proliferation / Translocation of SLC2A4 (GLUT4) to the plasma membrane / TP53 Regulates Metabolic Genes / RAF activation / cellular response to nerve growth factor stimulus / Spry regulation of FGF signaling / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / visual learning / response to peptide hormone / centriolar satellite / long-term synaptic potentiation / epidermal growth factor receptor signaling pathway / intrinsic apoptotic signaling pathway in response to DNA damage / Signaling by RAF1 mutants / Negative regulation of MAPK pathway / 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 / MAPK cascade / intracellular protein localization / cellular response to xenobiotic stimulus / presynapse / T cell receptor signaling pathway / regulation of protein localization / regulation of cell population proliferation / T cell differentiation in thymus / cell body / positive regulation of cell growth / scaffold protein binding / negative regulation of neuron apoptotic process / eukaryotic translation initiation factor 2alpha kinase activity / 3-phosphoinositide-dependent protein kinase activity / DNA-dependent protein kinase activity
Similarity search - Function
Raf-like Ras-binding domain / Raf-like Ras-binding / Ras-binding domain (RBD) profile. / Raf-like Ras-binding domain / Diacylglycerol/phorbol-ester binding / : / Phorbol esters/diacylglycerol binding domain (C1 domain) / Zinc finger phorbol-ester/DAG-type signature. / 14-3-3 protein sigma / Zinc finger phorbol-ester/DAG-type profile. ...Raf-like Ras-binding domain / Raf-like Ras-binding / Ras-binding domain (RBD) profile. / Raf-like Ras-binding domain / Diacylglycerol/phorbol-ester binding / : / Phorbol esters/diacylglycerol binding domain (C1 domain) / Zinc finger phorbol-ester/DAG-type signature. / 14-3-3 protein sigma / Zinc finger phorbol-ester/DAG-type profile. / Protein kinase C conserved region 1 (C1) domains (Cysteine-rich domains) / Protein kinase C-like, phorbol ester/diacylglycerol-binding domain / C1-like domain superfamily / 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 / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Ubiquitin-like domain superfamily / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Serine/threonine-protein kinase B-raf / 14-3-3 protein sigma
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.65 Å
AuthorsKonstantinidou, M. / Vickery, H. / Pennings, M.A.M. / Virta, J. / Visser, E.J. / Oetelaar, M.C.M. / Overmans, M. / Neitz, J. / Ottmann, C. / Brunsveld, L. / 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: To Be Published
Title: Small molecule stabilization of the 14-3-3sigma/CRAF complex inhibits the MAPK pathway
Authors: Konstantinidou, M. / Vickery, H. / Pennings, M.A.M. / Virta, J. / Visser, E.J. / Oetelaar, M.C.M. / Overmans, M. / Neitz, J. / Ottmann, C. / Brunsveld, L. / Arkin, M.R.
History
DepositionApr 3, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 16, 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
P: Serine/threonine-protein kinase B-raf
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,6515
Polymers27,5562
Non-polymers953
Water3,351186
1
A: 14-3-3 protein sigma
P: Serine/threonine-protein kinase B-raf
hetero molecules

A: 14-3-3 protein sigma
P: Serine/threonine-protein kinase B-raf
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,30210
Polymers55,1124
Non-polymers1906
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_555x,-y,-z1
Buried area5060 Å2
ΔGint-71 kcal/mol
Surface area22470 Å2
MethodPISA
Unit cell
Length a, b, c (Å)81.783, 96.043, 80.440
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 Serine/threonine-protein kinase B-raf / Proto-oncogene B-Raf / p94 / v-Raf murine sarcoma viral oncogene homolog B1


Mass: 1012.935 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
References: UniProt: P15056, non-specific serine/threonine protein kinase
#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 186 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN
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: 2.97 Å3/Da / Density % sol: 58.52 %
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: ID30B / Wavelength: 0.873128 Å
DetectorType: DECTRIS EIGER2 X 9M / Detector: PIXEL / Date: Feb 19, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.873128 Å / Relative weight: 1
ReflectionResolution: 1.65→80.44 Å / Num. obs: 38175 / % possible obs: 99.3 % / Redundancy: 13.5 % / CC1/2: 0.998 / Net I/σ(I): 14.4
Reflection shellResolution: 1.65→1.68 Å / Mean I/σ(I) obs: 1.4 / Num. unique obs: 1908 / CC1/2: 0.694

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Processing

Software
NameClassification
PDB-REDOrefinement
autoPROCdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.65→62.27 Å / Cor.coef. Fo:Fc: 0.966 / Cor.coef. Fo:Fc free: 0.958 / SU B: 6.792 / SU ML: 0.094 / Cross valid method: THROUGHOUT / ESU R: 0.107 / ESU R Free: 0.089 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.221 1933 5.1 %RANDOM
Rwork0.18484 ---
obs0.18669 36201 99.18 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1 Å / Solvent model: MASK
Displacement parametersBiso mean: 37.648 Å2
Baniso -1Baniso -2Baniso -3
1--0.4 Å2-0 Å20 Å2
2---5.69 Å2-0 Å2
3---6.1 Å2
Refinement stepCycle: LAST / Resolution: 1.65→62.27 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1866 0 3 186 2055
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0161905
X-RAY DIFFRACTIONr_bond_other_d0.0010.0161808
X-RAY DIFFRACTIONr_angle_refined_deg1.2951.8222570
X-RAY DIFFRACTIONr_angle_other_deg0.4991.5694178
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2485.277253
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.89110357
X-RAY DIFFRACTIONr_chiral_restr0.0670.2285
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.022237
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02415
X-RAY DIFFRACTIONr_mcbond_it6.2243.534947
X-RAY DIFFRACTIONr_mcbond_other6.2123.534947
X-RAY DIFFRACTIONr_mcangle_it9.056.351180
X-RAY DIFFRACTIONr_mcangle_other9.0496.3531181
X-RAY DIFFRACTIONr_scbond_it7.133.875958
X-RAY DIFFRACTIONr_scbond_other7.1123.876958
X-RAY DIFFRACTIONr_scangle_other10.5746.9861388
X-RAY DIFFRACTIONr_long_range_B_refined16.65635.92257
X-RAY DIFFRACTIONr_long_range_B_other15.64634.452213
X-RAY DIFFRACTIONr_rigid_bond_restr4.20533713
LS refinement shellResolution: 1.65→1.693 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.374 139 -
Rwork0.362 2650 -
obs--99.68 %

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