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- PDB-8a6h: Small molecule stabilizer (compound 7) for C-RAF and 14-3-3 -

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Basic information

Entry
Database: PDB / ID: 8a6h
TitleSmall molecule stabilizer (compound 7) for C-RAF and 14-3-3
Components
  • 14-3-3 protein sigma
  • RAF proto-oncogene serine/threonine-protein kinase
KeywordsSTRUCTURAL PROTEIN / 14-3-3 / C-RAF / Stabilization
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 / protein kinase A signaling / response to muscle stretch / 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-L6L / 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
AuthorsKenanova, D.N. / Visser, E.J. / Virta, J. / Sijbesma, E. / Centorrino, F. / Zhong, M. / Vickery, H. / Neitz, J. / Brunsveld, L. / Ottmann, C. / Arkin, M.R.
Funding support Netherlands, 1items
OrganizationGrant numberCountry
Netherlands Organisation for Scientific Research (NWO)024.001.035 Netherlands
CitationJournal: Acs Cent.Sci. / Year: 2023
Title: A Systematic Approach to the Discovery of Protein-Protein Interaction Stabilizers.
Authors: Kenanova, D.N. / Visser, E.J. / Virta, J.M. / Sijbesma, E. / Centorrino, F. / Vickery, H.R. / Zhong, M. / Neitz, R.J. / Brunsveld, L. / Ottmann, C. / Arkin, M.R.
History
DepositionJun 17, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 26, 2023Provider: repository / Type: Initial release
Revision 1.1Jun 7, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Feb 7, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)28,2706
Polymers27,7492
Non-polymers5214
Water6,395355
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)56,53912
Polymers55,4984
Non-polymers1,0418
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_555x,-y,-z1
Buried area5990 Å2
ΔGint-70 kcal/mol
Surface area23850 Å2
MethodPISA
Unit cell
Length a, b, c (Å)82.499, 112.234, 62.756
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221

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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: 1206.183 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, 359 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.: 2 / Source method: obtained synthetically / Formula: Mg
#5: Chemical ChemComp-L6L / 3-[2-(dimethylamino)ethyldisulfanyl]-1-[4-oxidanyl-4-[3-(trifluoromethyl)phenyl]piperidin-1-yl]propan-1-one


Mass: 436.555 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H27F3N2O2S2 / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 355 / 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: 2.62 Å3/Da / Density % sol: 53.01 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 0.095 M HEPES pH 7.7, 0.19 M CaCl2, 24 % (v/v) PEG 400 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: 1.0332 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: 1.0332 Å / Relative weight: 1
ReflectionResolution: 1.6→45.63 Å / Num. obs: 522752 / % possible obs: 99.6 % / Redundancy: 13.5 % / CC1/2: 1 / Net I/σ(I): 42.6
Reflection shellResolution: 1.6→1.63 Å / Num. unique obs: 1878 / CC1/2: 0.995

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3iqu

3iqu


Resolution: 1.6→45.63 Å / SU ML: 0.12 / Cross valid method: THROUGHOUT / σ(F): 1.37 / Phase error: 16.64 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1738 3762 5.08 %
Rwork0.1527 70230 -
obs0.1537 73992 99.51 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 89.96 Å2 / Biso mean: 19.1275 Å2 / Biso min: 4.25 Å2
Refinement stepCycle: final / Resolution: 1.6→45.63 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1935 0 43 355 2333
Biso mean--27.18 28.45 -
Num. residues----247
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 27

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.6-1.620.18861690.14792595276498
1.62-1.640.1831170.14762566268399
1.64-1.660.17981690.14732562273199
1.66-1.690.17821410.14612581272299
1.69-1.710.16471410.141626122753100
1.71-1.740.16911340.154226492783100
1.74-1.770.1651260.14862576270299
1.77-1.80.18611120.1572643275599
1.8-1.830.27021610.16225772738100
1.83-1.870.16271250.159726022727100
1.87-1.90.2231270.15926212748100
1.9-1.950.19131640.150425862750100
1.95-1.990.1931300.149926552785100
1.99-2.040.15741330.153125752708100
2.04-2.10.19341300.142326122742100
2.1-2.160.20271460.143925972743100
2.16-2.230.14391240.14292629275399
2.23-2.310.15911370.13852540267798
2.31-2.40.17571510.134226322783100
2.4-2.510.1431310.150926012732100
2.51-2.640.15611290.145926132742100
2.64-2.810.15471440.150926012745100
2.81-3.020.18851410.158926352776100
3.02-3.330.19731820.15325772759100
3.33-3.810.13781290.149626102739100
3.81-4.80.1651320.14612556268898
4.8-45.630.17861370.198526272764100

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