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- PDB-8ats: Small molecular stabilizer for C-RAF (pS259) and 14-3-3 (1075306) -

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Basic information

Entry
Database: PDB / ID: 8ats
TitleSmall molecular stabilizer for C-RAF (pS259) and 14-3-3 (1075306)
Components
  • 14-3-3 protein sigma
  • RAF proto-oncogene serine/threonine-protein kinase
KeywordsSTRUCTURAL PROTEIN / 14-3-3 / ERalpha / stabilization / covalent
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 / regulation of cell motility / insulin secretion involved in cellular response to glucose stimulus / Negative feedback regulation of MAPK pathway ...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 / regulation of cell motility / insulin secretion involved in cellular response to glucose stimulus / Negative feedback regulation of MAPK pathway / GP1b-IX-V activation signalling / IFNG signaling activates MAPKs / regulation of epidermal cell division / protein kinase C inhibitor activity / regulation of cell differentiation / positive regulation of epidermal cell differentiation / keratinocyte development / ERBB2-ERBB3 signaling pathway / keratinization / face development / regulation of cell-cell adhesion / pseudopodium / neurotrophin TRK receptor signaling pathway / somatic stem cell population maintenance / thyroid gland development / Regulation of localization of FOXO transcription factors / keratinocyte proliferation / phosphoserine residue binding / negative regulation of keratinocyte proliferation / MAP kinase kinase kinase activity / extrinsic apoptotic signaling pathway via death domain receptors / Activation of BAD and translocation to mitochondria / 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 / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / Schwann cell development / activation of adenylate cyclase activity / 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 / positive regulation of protein localization / RHO GTPases activate PKNs / negative regulation of innate immune response / protein sequestering activity / response to muscle stretch / protein kinase A signaling / myelination / protein export from nucleus / CD209 (DC-SIGN) signaling / positive regulation of cell adhesion / release of cytochrome c from mitochondria / : / TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest / insulin-like growth factor receptor signaling pathway / thymus development / positive regulation of protein export from nucleus / stem cell proliferation / Translocation of SLC2A4 (GLUT4) to the plasma membrane / TP53 Regulates Metabolic Genes / RAF activation / negative regulation of protein kinase activity / 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 / 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 / MAPK cascade / protein localization / insulin receptor signaling pathway / positive regulation of peptidyl-serine phosphorylation / regulation of protein localization / positive regulation of cell growth / regulation of apoptotic process / mitochondrial outer membrane / positive regulation of MAPK cascade / non-specific serine/threonine protein kinase / regulation of cell cycle / protein kinase activity / cadherin binding / protein phosphorylation / negative regulation of cell population proliferation / protein serine kinase activity / protein serine/threonine kinase activity / negative regulation of apoptotic process / apoptotic process / protein kinase binding / Golgi apparatus / negative regulation of transcription by RNA polymerase II / enzyme binding / signal transduction / positive regulation of transcription by RNA polymerase II
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) / 14-3-3 protein sigma / Zinc finger phorbol-ester/DAG-type signature. / 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) / 14-3-3 protein sigma / Zinc finger phorbol-ester/DAG-type signature. / 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
Chem-O5I / 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: 1.4 Å
AuthorsVisser, E.J. / Overmans, M.J.A.M. / Vandenboorn, E.M.F. / Ottmann, C.
Funding support Netherlands, 1items
OrganizationGrant numberCountry
Netherlands Organisation for Scientific Research (NWO) 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
DepositionAug 24, 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
P: RAF proto-oncogene serine/threonine-protein kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,1347
Polymers27,6132
Non-polymers5215
Water3,297183
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)56,26714
Polymers55,2264
Non-polymers1,04110
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_555x,-y,-z1
Unit cell
Length a, b, c (Å)81.627, 112.368, 62.575
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, 188 molecules

#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Mg
#5: 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
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 183 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.6 Å3/Da / Density % sol: 52.66 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 0.095 M HEPES (pH 7.1), PEG400 (24% (v/v)), 0.19 M CaCl2 and 5% (v/v) Glycerol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: PETRA III, DESY / Beamline: P11 / Wavelength: 1.03322 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Nov 4, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.03322 Å / Relative weight: 1
ReflectionResolution: 1.4→45.46 Å / Num. obs: 56825 / % possible obs: 99.8 % / Redundancy: 1.9 % / CC1/2: 1 / Net I/σ(I): 25.2
Reflection shellResolution: 1.4→1.42 Å / Num. unique obs: 2721 / CC1/2: 0.889

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
XDSdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3iqu

3iqu


Resolution: 1.4→45.46 Å / Cor.coef. Fo:Fc: 0.97 / Cor.coef. Fo:Fc free: 0.968 / SU B: 1.57 / SU ML: 0.028 / Cross valid method: THROUGHOUT / ESU R: 0.052 / ESU R Free: 0.048 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.1706 2902 5.1 %RANDOM
Rwork0.14693 ---
obs0.14819 53923 99.78 %-
Solvent computationIon probe radii: 0.7 Å / Shrinkage radii: 0.7 Å / VDW probe radii: 1.1 Å / Solvent model: MASK
Displacement parametersBiso mean: 22.614 Å2
Baniso -1Baniso -2Baniso -3
1-1.87 Å20 Å2-0 Å2
2---0.86 Å20 Å2
3----1.01 Å2
Refinement stepCycle: LAST / Resolution: 1.4→45.46 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1930 0 30 183 2143
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0171985
X-RAY DIFFRACTIONr_bond_other_d0.0020.0191880
X-RAY DIFFRACTIONr_angle_refined_deg1.3221.8982672
X-RAY DIFFRACTIONr_angle_other_deg1.262.6994347
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.5085243
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.81422.569109
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.40215368
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.0261514
X-RAY DIFFRACTIONr_chiral_restr0.0820.2292
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.022232
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02428
X-RAY DIFFRACTIONr_mcbond_it1.8662.004978
X-RAY DIFFRACTIONr_mcbond_other1.8542.002977
X-RAY DIFFRACTIONr_mcangle_it2.5933.0071219
X-RAY DIFFRACTIONr_mcangle_other2.5943.0091220
X-RAY DIFFRACTIONr_scbond_it2.5732.3771007
X-RAY DIFFRACTIONr_scbond_other2.5712.3781008
X-RAY DIFFRACTIONr_scangle_other3.3843.431454
X-RAY DIFFRACTIONr_long_range_B_refined3.80224.322353
X-RAY DIFFRACTIONr_long_range_B_other3.70824.0462327
X-RAY DIFFRACTIONr_rigid_bond_restr1.50133865
LS refinement shellResolution: 1.4→1.436 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.245 189 -
Rwork0.197 3910 -
obs--97.92 %

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