|Entry||Database: PDB / ID: 6nyb|
|Title||Structure of a MAPK pathway complex|
|Function / homology|
Function and homology information
Spry regulation of FGF signaling / MAPK3 (ERK1) activation / Signalling to p38 via RIT and RIN / ARMS-mediated activation / Signal transduction by L1 / Uptake and function of anthrax toxins / RAF activation / MAP2K and MAPK activation / Negative feedback regulation of MAPK pathway / Negative regulation of MAPK pathway ...Spry regulation of FGF signaling / MAPK3 (ERK1) activation / Signalling to p38 via RIT and RIN / ARMS-mediated activation / Signal transduction by L1 / Uptake and function of anthrax toxins / RAF activation / MAP2K and MAPK activation / Negative feedback regulation of MAPK pathway / Negative regulation of MAPK pathway / MAP3K8 (TPL2)-dependent MAPK1/3 activation / Signaling by moderate kinase activity BRAF mutants / Frs2-mediated activation / Signaling by high-kinase activity BRAF mutants / Signaling by RAS mutants / Signaling by BRAF and RAF fusions / Paradoxical activation of RAF signaling by kinase inactive BRAF / epithelial cell proliferation involved in lung morphogenesis / labyrinthine layer development / mitogen-activated protein kinase kinase / placenta blood vessel development / trehalose metabolism in response to stress / regulation of axon regeneration / cerebellar cortex formation / positive regulation of glucose transmembrane transport / establishment of protein localization to membrane / regulation of Golgi inheritance / trachea formation / face development / regulation of early endosome to late endosome transport / positive regulation of axonogenesis / thyroid gland development / regulation of stress-activated MAPK cascade / cellular senescence / Bergmann glial cell differentiation / signal transduction by protein phosphorylation / positive regulation of production of miRNAs involved in gene silencing by miRNA / cell motility / protein serine/threonine kinase activator activity / stress-activated protein kinase signaling cascade / ERK1 and ERK2 cascade / MAP kinase kinase activity / keratinocyte differentiation / positive regulation of protein serine/threonine kinase activity / cellular response to calcium ion / protein serine/threonine/tyrosine kinase activity / activation of protein kinase activity / thymus development / neuron differentiation / animal organ morphogenesis / microtubule organizing center / cell cycle arrest / late endosome / scaffold protein binding / chemotaxis / heart development / peptidyl-threonine phosphorylation / positive regulation of peptidyl-serine phosphorylation / protein N-terminus binding / protein tyrosine kinase activity / activation of MAPK activity / protein C-terminus binding / early endosome / positive regulation of ERK1 and ERK2 cascade / negative regulation of gene expression / non-specific serine/threonine protein kinase / MAPK cascade / protein kinase activity / intracellular membrane-bounded organelle / negative regulation of cell population proliferation / focal adhesion / protein domain specific binding / protein serine/threonine kinase activity / positive regulation of gene expression / protein phosphorylation / calcium ion binding / positive regulation of transcription, DNA-templated / negative regulation of apoptotic process / endoplasmic reticulum / Golgi apparatus / signal transduction / mitochondrion / ATP binding / identical protein binding / plasma membrane / nucleus / cytosol / cytoplasm
Serine/Threonine protein kinases active-site signature. / Protein kinase-like domain superfamily / Ras-binding domain (RBD) profile. / Zinc finger phorbol-ester/DAG-type profile. / Zinc finger phorbol-ester/DAG-type signature. / 14-3-3 proteins signature 2. / 14-3-3 proteins signature 1. / 14-3-3 protein / Protein kinase domain / Serine-threonine/tyrosine-protein kinase, catalytic domain ...Serine/Threonine protein kinases active-site signature. / Protein kinase-like domain superfamily / Ras-binding domain (RBD) profile. / Zinc finger phorbol-ester/DAG-type profile. / Zinc finger phorbol-ester/DAG-type signature. / 14-3-3 proteins signature 2. / 14-3-3 proteins signature 1. / 14-3-3 protein / Protein kinase domain / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein kinase C-like, phorbol ester/diacylglycerol-binding domain / Raf-like Ras-binding / Serine/threonine-protein kinase, active site / Protein kinase, ATP binding site / Diacylglycerol/phorbol-ester binding / 14-3-3 protein, conserved site / 14-3-3 domain / Ubiquitin-like domain superfamily / 14-3-3 domain superfamily / Protein kinase domain / Phorbol esters/diacylglycerol binding domain (C1 domain) / 14-3-3 protein / Raf-like Ras-binding domain / Protein tyrosine kinase / Protein kinases ATP-binding region signature. / Protein kinase domain profile.
Serine/threonine-protein kinase B-raf / Dual specificity mitogen-activated protein kinase kinase 1 / 14-3-3 protein zeta
|Biological species||Homo sapiens (human)|
Spodoptera exigua (beet armyworm)
|Method||ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.1 Å|
|Authors||Park, E. / Rawson, S. / Li, K. / Jeon, H. / Eck, M.J.|
|Funding support|| United States, 2items |
|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 signaling 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 signaling 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. At present, the structural basis of RAF regulation is poorly understood. Here we describe autoinhibited and active state structures of full-length BRAF in complexes with MEK1 and a 14-3-3 dimer, determined using cryo-electron microscopy (cryo-EM). A 4.1 Å resolution cryo-EM 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 (CRD) occupies a central position that stabilizes this assembly, but the adjacent RAS-binding domain (RBD) is poorly ordered and peripheral. The 14-3-3 cradle maintains autoinhibition by sequestering the membrane-binding CRD 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, driving 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.
SummaryFull reportAbout validation report
|Structure viewer||Molecule: |
Downloads & links
A: Serine/threonine-protein kinase B-raf
B: Dual specificity mitogen-activated protein kinase kinase 1
C: 14-3-3 protein zeta
D: 14-3-3 protein zeta
-Protein/peptide , 3 types, 4 molecules A
B C D
|#1: Protein/peptide|| |
Mass: 89402.789 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRAF, BRAF1, RAFB1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P15056, non-specific serine/threonine protein kinase
|#2: Protein/peptide|| |
Mass: 45934.543 Da / Num. of mol.: 1 / Details: GDC-0623 / Mutation: S218A, S222A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAP2K1, MEK1, PRKMK1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q02750, mitogen-activated protein kinase kinase
Mass: 28108.514 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Spodoptera exigua (beet armyworm) / References: UniProt: V9P4T4
-Non-polymers , 5 types, 6 molecules
|#4: Chemical|| ChemComp-AGS / |
|#5: Chemical||#6: Chemical|| ChemComp-ADP / ||#7: Chemical|| ChemComp-MG / ||#8: Chemical|| ChemComp-LCJ / |
|Experiment||Method: ELECTRON MICROSCOPY|
|EM experiment||Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction|
|Component||Name: Ternary complex of BRAF/MEK1/14-3-3 with MEK inhibitor|
Details: 14-3-3 is heterodimer of Insect epsilon and zeta. model was generated by Insect zeta sequence as a homo-dimer.
Entity ID: 1, 2, 3 / Source: MULTIPLE SOURCES
|Molecular weight||Value: 0.19 MDa / Experimental value: YES|
|Source (natural)||Organism: Homo sapiens (human)|
|Buffer solution||pH: 7.4|
|Specimen||Conc.: 0.05 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES|
|Specimen support||Details: unspecified|
|Vitrification||Cryogen name: ETHANE|
-Electron microscopy imaging
Model: Titan Krios / Image courtesy: FEI Company
|Microscopy||Model: FEI TITAN KRIOS|
|Electron gun||Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER|
|Electron lens||Mode: OTHER / Cs: 2.7 mm / C2 aperture diameter: 70 µm|
|Image recording||Electron dose: 50 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)|
|Software||Name: PHENIX / Version: 1.15.2_3472: / Classification: refinement|
|CTF correction||Type: PHASE FLIPPING AND AMPLITUDE CORRECTION|
|3D reconstruction||Resolution: 4.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 165298 / Symmetry type: POINT|
|Refine LS restraints|
Refinement-ID: ELECTRON MICROSCOPY
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