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- PDB-9ew4: Ternary structure of 14-3-3s, C-RAF phosphopeptide 12mer (pS259) ... -

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Basic information

Entry
Database: PDB / ID: 9ew4
TitleTernary structure of 14-3-3s, C-RAF phosphopeptide 12mer (pS259) and compound 86 (1124384)
Components
  • 14-3-3 protein sigma
  • RAF proto-oncogene serine/threonine-protein kinase
KeywordsPEPTIDE BINDING PROTEIN / Stabilizer / protein-protein interaction
Function / homology
Function and homology information


death-inducing signaling complex assembly / intermediate filament cytoskeleton organization / type B pancreatic cell proliferation / regulation of Rho protein signal transduction / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / Rap1 signalling / insulin secretion involved in cellular response to glucose stimulus / Negative feedback regulation of MAPK pathway / IFNG signaling activates MAPKs ...death-inducing signaling complex assembly / intermediate filament cytoskeleton organization / type B pancreatic cell proliferation / regulation of Rho protein signal transduction / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / Rap1 signalling / insulin secretion involved in cellular response to glucose stimulus / Negative feedback regulation of MAPK pathway / IFNG signaling activates MAPKs / GP1b-IX-V activation signalling / regulation of epidermal cell division / protein kinase C inhibitor activity / positive regulation of epidermal cell differentiation / keratinocyte development / ERBB2-ERBB3 signaling pathway / keratinization / regulation of cell-cell adhesion / face development / pseudopodium / neurotrophin TRK receptor signaling pathway / regulation of cell differentiation / thyroid gland development / cAMP/PKA signal transduction / Regulation of localization of FOXO transcription factors / somatic stem cell population maintenance / keratinocyte proliferation / extrinsic apoptotic signaling pathway via death domain receptors / phosphoserine residue binding / MAP kinase kinase kinase activity / Activation of BAD and translocation to mitochondria / type II interferon-mediated signaling pathway / negative regulation of keratinocyte proliferation / establishment of skin barrier / negative regulation of protein localization to plasma membrane / negative regulation of protein-containing complex assembly / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / Schwann cell development / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / negative regulation of stem cell proliferation / SARS-CoV-1 targets host intracellular signalling and regulatory pathways / RHO GTPases activate PKNs / activation of adenylate cyclase activity / positive regulation of peptidyl-serine phosphorylation / positive regulation of protein localization / response to muscle stretch / myelination / CD209 (DC-SIGN) signaling / positive regulation of cell adhesion / protein sequestering activity / insulin-like growth factor receptor signaling pathway / 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 / negative regulation of protein kinase activity / stem cell proliferation / Translocation of SLC2A4 (GLUT4) to the plasma membrane / TP53 Regulates Metabolic Genes / RAF activation / wound healing / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / Stimuli-sensing channels / 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 / insulin receptor signaling pathway / regulation of protein localization / positive regulation of cell growth / regulation of apoptotic process / mitochondrial outer membrane / eukaryotic translation initiation factor 2alpha kinase activity / 3-phosphoinositide-dependent protein kinase activity / DNA-dependent protein kinase activity / ribosomal protein S6 kinase activity / histone H3S10 kinase activity / histone H2AXS139 kinase activity / histone H3S28 kinase activity / histone H4S1 kinase activity / histone H2BS14 kinase activity / histone H3T3 kinase activity / histone H2AS121 kinase activity / Rho-dependent protein serine/threonine kinase activity / histone H2BS36 kinase activity / histone H3S57 kinase activity / histone H2AT120 kinase activity / AMP-activated protein kinase activity / histone H2AS1 kinase activity / histone H3T6 kinase activity / histone H3T11 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 / Ubiquitin-like domain superfamily / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / 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
: / RAF proto-oncogene serine/threonine-protein kinase / 14-3-3 protein sigma
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 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: RAF proto-oncogene serine/threonine-protein kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,1858
Polymers27,6132
Non-polymers5726
Water3,945219
1
A: 14-3-3 protein sigma
P: RAF proto-oncogene serine/threonine-protein kinase
hetero molecules

A: 14-3-3 protein sigma
P: RAF proto-oncogene serine/threonine-protein kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,37116
Polymers55,2264
Non-polymers1,14512
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_555x,-y,-z1
Buried area5750 Å2
ΔGint-79 kcal/mol
Surface area24020 Å2
MethodPISA
Unit cell
Length a, b, c (Å)81.874, 112.610, 62.992
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-304-

MG

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Components

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Protein / Protein/peptide , 2 types, 2 molecules AP

#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 RAF proto-oncogene serine/threonine-protein kinase / Proto-oncogene c-RAF / cRaf / Raf-1


Mass: 1070.028 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
References: UniProt: P04049, non-specific serine/threonine protein kinase

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Non-polymers , 4 types, 225 molecules

#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: Cl
#4: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Mg
#5: Chemical ChemComp-WQ9 / 1-[(5~{R})-2-(4-bromanyl-3-fluoranyl-phenyl)sulfonyl-2,7-diazaspiro[4.4]nonan-7-yl]-2-chloranyl-ethanone


Mass: 439.727 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H17BrClFN2O3S / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 219 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.63 Å3/Da / Density % sol: 53.19 %
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 EIGER2 X 9M / Detector: PIXEL / Date: Nov 16, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.873128 Å / Relative weight: 1
ReflectionResolution: 1.6→62.99 Å / Num. obs: 38411 / % possible obs: 99 % / Redundancy: 11.7 % / CC1/2: 0.997 / Net I/σ(I): 9.3
Reflection shellResolution: 1.6→1.63 Å / Mean I/σ(I) obs: 1.2 / Num. unique obs: 1903 / CC1/2: 0.496

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Processing

Software
NameClassification
PDB-REDOrefinement
autoPROCdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.6→56.37 Å / Cor.coef. Fo:Fc: 0.965 / Cor.coef. Fo:Fc free: 0.946 / SU B: 1.976 / SU ML: 0.065 / Cross valid method: THROUGHOUT / ESU R: 0.083 / ESU R Free: 0.084 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.21092 1962 5.1 %RANDOM
Rwork0.17963 ---
obs0.18119 36427 98.9 %-
Solvent computationIon probe radii: 1 Å / Shrinkage radii: 1 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 22.627 Å2
Baniso -1Baniso -2Baniso -3
1-1.55 Å20 Å2-0 Å2
2---0.62 Å20 Å2
3----0.93 Å2
Refinement stepCycle: LAST / Resolution: 1.6→56.37 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1929 0 28 219 2176
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0170.0161994
X-RAY DIFFRACTIONr_bond_other_d0.0010.0161884
X-RAY DIFFRACTIONr_angle_refined_deg3.7151.8382704
X-RAY DIFFRACTIONr_angle_other_deg0.5611.5674357
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.7415.288260
X-RAY DIFFRACTIONr_dihedral_angle_2_deg4.079202
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.25210372
X-RAY DIFFRACTIONr_chiral_restr0.1220.2297
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.022314
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02430
X-RAY DIFFRACTIONr_mcbond_it2.031.998982
X-RAY DIFFRACTIONr_mcbond_other2.0251.998982
X-RAY DIFFRACTIONr_mcangle_it3.1053.8211225
X-RAY DIFFRACTIONr_mcangle_other3.0973.6551223
X-RAY DIFFRACTIONr_scbond_it3.3842.3991012
X-RAY DIFFRACTIONr_scbond_other3.3822.3991013
X-RAY DIFFRACTIONr_scangle_other5.2794.5611478
X-RAY DIFFRACTIONr_long_range_B_refined6.83823.872399
X-RAY DIFFRACTIONr_long_range_B_other6.75922.742336
LS refinement shellResolution: 1.6→1.641 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.275 154 -
Rwork0.294 2705 -
obs--99.83 %

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