[English] 日本語
Yorodumi
- PDB-8a6f: Small molecule stabilizer (compound 8) for C-RAF and 14-3-3 -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 8a6f
TitleSmall molecule stabilizer (compound 8) 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 / 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 / 14-3-3 domain / Delta-Endotoxin; domain 1 / : / Phorbol esters/diacylglycerol binding domain (C1 domain) / Zinc finger phorbol-ester/DAG-type signature. ...Raf-like Ras-binding domain / Raf-like Ras-binding / Ras-binding domain (RBD) profile. / Raf-like Ras-binding domain / Diacylglycerol/phorbol-ester binding / 14-3-3 domain / Delta-Endotoxin; domain 1 / : / 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 / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-O56 / 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
Revision 1.3Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
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)28,3046
Polymers27,7492
Non-polymers5554
Water5,981332
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)56,60812
Polymers55,4984
Non-polymers1,1108
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_555x,-y,-z1
Buried area6130 Å2
ΔGint-69 kcal/mol
Surface area24030 Å2
MethodPISA
Unit cell
Length a, b, c (Å)82.944, 112.909, 62.794
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11A-651-

HOH

-
Components

-
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

-
Non-polymers , 4 types, 336 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-O56 / 1-[4-[4-chloranyl-3-(trifluoromethyl)phenyl]-4-oxidanyl-piperidin-1-yl]-3-[2-(dimethylamino)ethyldisulfanyl]propan-1-one


Mass: 471.000 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H26ClF3N2O2S2 / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 332 / Source method: isolated from a natural source / Formula: H2O

-
Details

Has ligand of interestY
Has protein modificationY

-
Experimental details

-
Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

-
Sample preparation

CrystalDensity Matthews: 2.65 Å3/Da / Density % sol: 53.57 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 0.095 M HEPES pH 7.5, 0.19 M CaCl2, 26% (v/v) PEG 400 and 5% (v/v) glycerol

-
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→45.77 Å / Num. obs: 507054 / % possible obs: 100 % / Redundancy: 12.9 % / CC1/2: 0.996 / Net I/σ(I): 14.6
Reflection shellResolution: 1.6→1.63 Å / Num. unique obs: 1906 / CC1/2: 0.437

-
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→45.77 Å / SU ML: 0.15 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 18.45 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1809 3804 5.09 %
Rwork0.1622 70976 -
obs0.1632 74780 99.48 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 98.06 Å2 / Biso mean: 23.7068 Å2 / Biso min: 7.29 Å2
Refinement stepCycle: final / Resolution: 1.6→45.77 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1940 0 43 332 2315
Biso mean--33.21 31.59 -
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 (%)
1.6-1.620.2181520.18952519267197
1.62-1.640.20171230.19412519264295
1.64-1.660.23411530.18192584273798
1.66-1.690.24111620.18742641280399
1.69-1.710.2161550.19422589274499
1.71-1.740.18091100.18492667277799
1.74-1.770.18541440.18762591273599
1.77-1.80.21321160.18012703281999
1.8-1.830.24881540.172725842738100
1.83-1.870.18021240.169526192743100
1.87-1.90.19291340.173326522786100
1.9-1.950.22161730.160326602833100
1.95-1.990.18361110.158426412752100
1.99-2.040.18241400.168126642804100
2.04-2.10.17541310.156226332764100
2.1-2.160.21181520.16226162768100
2.16-2.230.16951310.148826512782100
2.23-2.310.16811390.146126742813100
2.31-2.40.18291530.142726252778100
2.4-2.510.16821360.151126692805100
2.51-2.640.16841360.152826392775100
2.64-2.810.15561400.163326402780100
2.81-3.020.20731410.162626402781100
3.02-3.330.19371780.157226182796100
3.33-3.810.14361370.152626182755100
3.81-4.80.15531340.140126722806100
4.8-45.770.17941450.201126482793100

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more