+Open data
-Basic information
Entry | Database: PDB / ID: 6q0k | |||||||||
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Title | Structure of a MAPK pathway complex | |||||||||
Components |
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Keywords | SIGNALING PROTEIN/Transferase / TRANSFERASE / SIGNALING PROTEIN-Transferase complex | |||||||||
Function / homology | Function and homology information Golgi reassembly / synaptic target recognition / respiratory system process / CD4-positive, alpha-beta T cell differentiation / NOTCH4 Activation and Transmission of Signal to the Nucleus / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / establishment of Golgi localization / negative regulation of synaptic vesicle exocytosis / Signalling to p38 via RIT and RIN / regulation of synapse maturation ...Golgi reassembly / synaptic target recognition / respiratory system process / CD4-positive, alpha-beta T cell differentiation / NOTCH4 Activation and Transmission of Signal to the Nucleus / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / establishment of Golgi localization / negative regulation of synaptic vesicle exocytosis / Signalling to p38 via RIT and RIN / regulation of synapse maturation / head morphogenesis / myeloid progenitor cell differentiation / tube formation / ARMS-mediated activation / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / endothelial cell apoptotic process / Rap1 signalling / negative regulation of fibroblast migration / positive regulation of glucose transmembrane transport / establishment of protein localization to membrane / negative regulation of protein localization to nucleus / MAP kinase kinase kinase activity / mitogen-activated protein kinase kinase binding / regulation of T cell differentiation / Negative feedback regulation of MAPK pathway / KSRP (KHSRP) binds and destabilizes mRNA / positive regulation of axonogenesis / GP1b-IX-V activation signalling / Frs2-mediated activation / stress fiber assembly / positive regulation of axon regeneration / face development / synaptic vesicle exocytosis / somatic stem cell population maintenance / MAP kinase kinase activity / thyroid gland development / Regulation of localization of FOXO transcription factors / phosphoserine residue binding / Interleukin-3, Interleukin-5 and GM-CSF signaling / Activation of BAD and translocation to mitochondria / protein targeting / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / negative regulation of endothelial cell apoptotic process / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / regulation of ERK1 and ERK2 cascade / cellular response to glucose starvation / SARS-CoV-1 targets host intracellular signalling and regulatory pathways / positive regulation of substrate adhesion-dependent cell spreading / RHO GTPases activate PKNs / positive regulation of stress fiber assembly / negative regulation of TORC1 signaling / response to cAMP / protein sequestering activity / cellular response to calcium ion / ERK1 and ERK2 cascade / negative regulation of innate immune response / hippocampal mossy fiber to CA3 synapse / substrate adhesion-dependent cell spreading / lung development / cellular response to nerve growth factor stimulus / thymus development / epidermal growth factor receptor signaling pathway / Translocation of SLC2A4 (GLUT4) to the plasma membrane / Deactivation of the beta-catenin transactivating complex / TP53 Regulates Metabolic Genes / long-term synaptic potentiation / animal organ morphogenesis / Negative regulation of NOTCH4 signaling / RAF activation / Spry regulation of FGF signaling / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / visual learning / regulation of protein stability / response to peptide hormone / cellular response to xenobiotic stimulus / 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 / positive regulation of peptidyl-serine phosphorylation / MAPK cascade / Signaling by BRAF and RAF1 fusions / protein localization / melanosome / presynapse / T cell receptor signaling pathway / regulation of cell population proliferation / cell body / T cell differentiation in thymus / DNA-binding transcription factor binding / scaffold protein binding / angiogenesis / vesicle / negative regulation of neuron apoptotic process / transmembrane transporter binding / positive regulation of ERK1 and ERK2 cascade / blood microparticle Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 6.8 Å | |||||||||
Authors | Park, E. / Rawson, S. / Jeon, H. / Eck, M.J. | |||||||||
Funding support | United States, 2items
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Citation | Journal: Nature / Year: 2019 Title: Architecture of autoinhibited and active BRAF-MEK1-14-3-3 complexes. Authors: Eunyoung Park / Shaun Rawson / Kunhua Li / Byeong-Won Kim / Scott B Ficarro / Gonzalo Gonzalez-Del Pino / Humayun Sharif / Jarrod A Marto / Hyesung Jeon / Michael J Eck / Abstract: RAF family kinases are RAS-activated switches that initiate signalling through the MAP kinase cascade to control cellular proliferation, differentiation and survival. RAF activity is tightly ...RAF family kinases are RAS-activated switches that initiate signalling through the MAP kinase cascade to control cellular proliferation, differentiation and survival. RAF activity is tightly regulated and inappropriate activation is a frequent cause of cancer; however, the structural basis for RAF regulation is poorly understood at present. Here we use cryo-electron microscopy to determine autoinhibited and active-state structures of full-length BRAF in complexes with MEK1 and a 14-3-3 dimer. The reconstruction reveals an inactive BRAF-MEK1 complex restrained in a cradle formed by the 14-3-3 dimer, which binds the phosphorylated S365 and S729 sites that flank the BRAF kinase domain. The BRAF cysteine-rich domain occupies a central position that stabilizes this assembly, but the adjacent RAS-binding domain is poorly ordered and peripheral. The 14-3-3 cradle maintains autoinhibition by sequestering the membrane-binding cysteine-rich domain and blocking dimerization of the BRAF kinase domain. In the active state, these inhibitory interactions are released and a single 14-3-3 dimer rearranges to bridge the C-terminal pS729 binding sites of two BRAFs, which drives the formation of an active, back-to-back BRAF dimer. Our structural snapshots provide a foundation for understanding normal RAF regulation and its mutational disruption in cancer and developmental syndromes. | |||||||||
History |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | Molecule: MolmilJmol/JSmol |
-Downloads & links
-Download
PDBx/mmCIF format | 6q0k.cif.gz | 178 KB | Display | PDBx/mmCIF format |
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PDB format | pdb6q0k.ent.gz | 117.9 KB | Display | PDB format |
PDBx/mmJSON format | 6q0k.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 6q0k_validation.pdf.gz | 710.9 KB | Display | wwPDB validaton report |
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Full document | 6q0k_full_validation.pdf.gz | 713.3 KB | Display | |
Data in XML | 6q0k_validation.xml.gz | 28.3 KB | Display | |
Data in CIF | 6q0k_validation.cif.gz | 43.6 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/q0/6q0k ftp://data.pdbj.org/pub/pdb/validation_reports/q0/6q0k | HTTPS FTP |
-Related structure data
Related structure data | 20551MC 0541C 6nybC 6pp9C 6q0jC 6q0tC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
#1: Protein | Mass: 89322.812 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: BRAF, BRAF1, RAFB1 / Production host: Homo sapiens (human) References: UniProt: P15056, non-specific serine/threonine protein kinase #2: Protein | Mass: 27777.092 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P63104 Has ligand of interest | Y | |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: ERK pathway complex / Type: COMPLEX / Entity ID: all / Source: MULTIPLE SOURCES |
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Molecular weight | Value: 233 kDa/nm / Experimental value: YES |
Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Spodoptera frugiperda (fall armyworm) |
Buffer solution | pH: 7.5 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Specimen support | Details: unspecified |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER |
Electron lens | Mode: OTHER |
Image recording | Electron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
-Processing
CTF correction | Type: NONE | ||||||||||||||||||||
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3D reconstruction | Resolution: 6.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 66215 / Symmetry type: POINT | ||||||||||||||||||||
Atomic model building | Protocol: RIGID BODY FIT / Space: REAL | ||||||||||||||||||||
Atomic model building |
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