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- PDB-9ew5: Ternary structure of 14-3-3s, C-RAF phosphopeptide (pS259) 12mer ... -

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Basic information

Entry
Database: PDB / ID: 9ew5
TitleTernary structure of 14-3-3s, C-RAF phosphopeptide (pS259) 12mer and compound 23 (1083848)
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 / regulation of Rho protein signal transduction / type B pancreatic cell proliferation / 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 / regulation of Rho protein signal transduction / type B pancreatic cell proliferation / 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 / ERBB2-ERBB3 signaling pathway / positive regulation of epidermal cell differentiation / keratinocyte development / keratinization / neurotrophin TRK receptor signaling pathway / pseudopodium / face development / regulation of cell-cell adhesion / regulation of cell differentiation / thyroid gland development / cAMP/PKA signal transduction / Regulation of localization of FOXO transcription factors / keratinocyte proliferation / extrinsic apoptotic signaling pathway via death domain receptors / somatic stem cell population maintenance / positive regulation of peptidyl-serine phosphorylation / Activation of BAD and translocation to mitochondria / phosphoserine residue binding / MAP kinase kinase kinase activity / negative regulation of keratinocyte proliferation / establishment of skin barrier / type II interferon-mediated signaling pathway / negative regulation of protein localization to plasma membrane / negative regulation of protein-containing complex assembly / Schwann cell development / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / negative regulation of protein kinase activity / negative regulation of stem cell proliferation / SARS-CoV-1 targets host intracellular signalling and regulatory pathways / RHO GTPases activate PKNs / positive regulation of protein localization / response to muscle stretch / myelination / CD209 (DC-SIGN) signaling / positive regulation of cell adhesion / insulin-like growth factor receptor signaling pathway / protein sequestering activity / protein export from nucleus / negative regulation of innate immune response / TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest / release of cytochrome c from mitochondria / thymus development / adenylate cyclase activator activity / positive regulation of protein export from nucleus / stem cell proliferation / TP53 Regulates Metabolic Genes / Translocation of SLC2A4 (GLUT4) to the plasma membrane / wound healing / RAF activation / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / Stimuli-sensing channels / intrinsic apoptotic signaling pathway in response to DNA damage / 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 / insulin receptor signaling pathway / intracellular protein localization / MAPK cascade / regulation of protein localization / positive regulation of cell growth / regulation of apoptotic process / mitochondrial outer membrane / protein phosphorylation / non-specific serine/threonine protein kinase / protein kinase activity / regulation of cell cycle / positive regulation of MAPK cascade / cadherin binding / negative regulation of cell population proliferation / protein serine kinase activity / protein serine/threonine kinase activity / apoptotic process / protein kinase binding / negative regulation of apoptotic process / enzyme binding / negative regulation of transcription by RNA polymerase II / Golgi apparatus / signal transduction / positive regulation of transcription by RNA polymerase II / mitochondrion / extracellular space
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: 1.5 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

Downloads & links

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Assembly

Deposited unit
A: 14-3-3 protein sigma
C: RAF proto-oncogene serine/threonine-protein kinase
D: 14-3-3 protein sigma
F: RAF proto-oncogene serine/threonine-protein kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,82310
Polymers55,7654
Non-polymers1,0586
Water7,873437
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5780 Å2
ΔGint-55 kcal/mol
Surface area22700 Å2
MethodPISA
Unit cell
Length a, b, c (Å)61.072, 90.017, 118.046
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP22121

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Components

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Protein / Protein/peptide , 2 types, 4 molecules ADCF

#1: Protein 14-3-3 protein sigma / Epithelial cell marker protein 1 / Stratifin


Mass: 26542.914 Da / Num. of mol.: 2
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: 1339.371 Da / Num. of mol.: 2 / 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, 443 molecules

#3: Chemical ChemComp-WQI / 2-chloranyl-~{N}-[[1-(4-iodophenyl)sulfonylpiperidin-4-yl]methyl]ethanamide


Mass: 456.727 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H18ClIN2O3S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 3 / Source method: isolated from a natural source / Formula: Ca
#5: Chemical ChemComp-MG / MAGNESIUM ION


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


Mass: 18.015 Da / Num. of mol.: 437 / 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: 2.94 Å3/Da / Density % sol: 58.2 %
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 CdTe 16M / 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: 1.5→61.07 Å / Num. obs: 104766 / % possible obs: 100 % / Redundancy: 13.3 % / CC1/2: 0.999 / Net I/σ(I): 12.8
Reflection shellResolution: 1.5→1.53 Å / Mean I/σ(I) obs: 1.2 / Num. unique obs: 5125 / CC1/2: 0.697

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Processing

Software
NameVersionClassification
REFMAC5.8.0425refinement
autoPROCdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.5→54.3 Å / Cor.coef. Fo:Fc: 0.965 / Cor.coef. Fo:Fc free: 0.956 / SU B: 1.442 / SU ML: 0.052 / Cross valid method: THROUGHOUT / ESU R: 0.066 / ESU R Free: 0.069 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.21621 5222 5 %RANDOM
Rwork0.19049 ---
obs0.1918 99472 99.98 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 29.161 Å2
Baniso -1Baniso -2Baniso -3
1--1.67 Å2-0 Å20 Å2
2--1.37 Å20 Å2
3---0.3 Å2
Refinement stepCycle: 1 / Resolution: 1.5→54.3 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3811 0 46 437 4294
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0123918
X-RAY DIFFRACTIONr_bond_other_d0.0010.0163717
X-RAY DIFFRACTIONr_angle_refined_deg1.7691.8565278
X-RAY DIFFRACTIONr_angle_other_deg0.6141.7798590
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.2745480
X-RAY DIFFRACTIONr_dihedral_angle_2_deg8.052530
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.2310733
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.0950.2585
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.024572
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02852
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.6172.6521926
X-RAY DIFFRACTIONr_mcbond_other2.6172.6511926
X-RAY DIFFRACTIONr_mcangle_it3.6024.752398
X-RAY DIFFRACTIONr_mcangle_other3.6044.752399
X-RAY DIFFRACTIONr_scbond_it3.8823.0331992
X-RAY DIFFRACTIONr_scbond_other3.8813.0341993
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other5.9285.3972879
X-RAY DIFFRACTIONr_long_range_B_refined6.87632.3316690
X-RAY DIFFRACTIONr_long_range_B_other6.75631.7616260
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.5→1.539 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.306 336 -
Rwork0.304 7270 -
obs--99.97 %

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