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- PDB-8a8m: Structure of the MAPK p38alpha in complex with its activating MAP... -
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Open data
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Basic information
Entry | Database: PDB / ID: 8a8m | ||||||
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Title | Structure of the MAPK p38alpha in complex with its activating MAP2K MKK6 | ||||||
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![]() | IMMUNE SYSTEM / Kinase / Signalling / MAP kinase / phosphoryl transfer | ||||||
Function / homology | ![]() cellular response to sorbitol / ovulation cycle process / nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway / positive regulation of prostaglandin secretion / mitogen-activated protein kinase kinase / positive regulation of cyclase activity / stress-activated protein kinase signaling cascade / negative regulation of cold-induced thermogenesis / Activation of PPARGC1A (PGC-1alpha) by phosphorylation / CD163 mediating an anti-inflammatory response ...cellular response to sorbitol / ovulation cycle process / nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway / positive regulation of prostaglandin secretion / mitogen-activated protein kinase kinase / positive regulation of cyclase activity / stress-activated protein kinase signaling cascade / negative regulation of cold-induced thermogenesis / Activation of PPARGC1A (PGC-1alpha) by phosphorylation / CD163 mediating an anti-inflammatory response / regulation of synaptic membrane adhesion / stress-induced premature senescence / cell surface receptor protein serine/threonine kinase signaling pathway / 3'-UTR-mediated mRNA stabilization / KSRP (KHSRP) binds and destabilizes mRNA / cartilage condensation / DSCAM interactions / cellular response to UV-B / Platelet sensitization by LDL / mitogen-activated protein kinase p38 binding / positive regulation of myoblast fusion / positive regulation of muscle cell differentiation / negative regulation of hippo signaling / positive regulation of myotube differentiation / NFAT protein binding / Myogenesis / Activation of the AP-1 family of transcription factors / ERK/MAPK targets / glucose import / regulation of cytokine production involved in inflammatory response / positive regulation of nitric-oxide synthase biosynthetic process / PI5P Regulates TP53 Acetylation / p38MAPK cascade / fatty acid oxidation / cellular response to lipoteichoic acid / MAP kinase kinase activity / response to dietary excess / response to muramyl dipeptide / Uptake and function of anthrax toxins / RHO GTPases Activate NADPH Oxidases / MAP kinase activity / regulation of ossification / mitogen-activated protein kinase / cellular response to vascular endothelial growth factor stimulus / signal transduction in response to DNA damage / positive regulation of myoblast differentiation / chondrocyte differentiation / vascular endothelial growth factor receptor signaling pathway / cardiac muscle contraction / stress-activated MAPK cascade / skeletal muscle tissue development / lipopolysaccharide-mediated signaling pathway / positive regulation of cardiac muscle cell proliferation / negative regulation of inflammatory response to antigenic stimulus / p38MAPK events / striated muscle cell differentiation / response to muscle stretch / positive regulation of interleukin-12 production / positive regulation of brown fat cell differentiation / osteoclast differentiation / positive regulation of erythrocyte differentiation / regulation of signal transduction by p53 class mediator / DNA damage checkpoint signaling / activated TAK1 mediates p38 MAPK activation / response to ischemia / cellular response to ionizing radiation / stem cell differentiation / positive regulation of glucose import / NOD1/2 Signaling Pathway / response to insulin / bone development / negative regulation of canonical Wnt signaling pathway / placenta development / PKR-mediated signaling / cell morphogenesis / platelet activation / cellular response to virus / VEGFA-VEGFR2 Pathway / spindle pole / positive regulation of protein import into nucleus / Interleukin-1 signaling / osteoblast differentiation / ADP signalling through P2Y purinoceptor 1 / glucose metabolic process / chemotaxis / positive regulation of reactive oxygen species metabolic process / MAPK cascade / cellular senescence / cellular response to tumor necrosis factor / cellular response to lipopolysaccharide / peptidyl-serine phosphorylation / protein phosphatase binding / protein tyrosine kinase activity / angiogenesis / Oxidative Stress Induced Senescence / secretory granule lumen / Regulation of TP53 Activity through Phosphorylation / ficolin-1-rich granule lumen / transcription by RNA polymerase II / positive regulation of MAPK cascade Similarity search - Function | ||||||
Biological species | ![]() | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4 Å | ||||||
![]() | Bowler, M.W. / Juyoux, P. / Pellegrini, E. | ||||||
Funding support | 1items
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![]() | ![]() Title: Architecture of the MKK6-p38α complex defines the basis of MAPK specificity and activation. Authors: Pauline Juyoux / Ioannis Galdadas / Dorothea Gobbo / Jill von Velsen / Martin Pelosse / Mark Tully / Oscar Vadas / Francesco Luigi Gervasio / Erika Pellegrini / Matthew W Bowler / ![]() ![]() ![]() Abstract: The mitogen-activated protein kinase (MAPK) p38α is a central component of signaling in inflammation and the immune response and is, therefore, an important drug target. Little is known about the ...The mitogen-activated protein kinase (MAPK) p38α is a central component of signaling in inflammation and the immune response and is, therefore, an important drug target. Little is known about the molecular mechanism of its activation by double phosphorylation from MAPK kinases (MAP2Ks), because of the challenge of trapping a transient and dynamic heterokinase complex. We applied a multidisciplinary approach to generate a structural model of p38α in complex with its MAP2K, MKK6, and to understand the activation mechanism. Integrating cryo-electron microscopy with molecular dynamics simulations, hydrogen-deuterium exchange mass spectrometry, and experiments in cells, we demonstrate a dynamic, multistep phosphorylation mechanism, identify catalytically relevant interactions, and show that MAP2K-disordered amino termini determine pathway specificity. Our work captures a fundamental step of cell signaling: a kinase phosphorylating its downstream target kinase. #1: ![]() Title: Architecture of the MKK6-p38 alpha complex defines the basis of MAPK specificity and activation Authors: Juyoux, P. / Galdadas, I. / Gobbo, D. / Tully, M. / Gervasio, F.L. / Pellegrini, E. / Bowler, M.W. | ||||||
History |
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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PDBx/mmCIF format | ![]() | 148.3 KB | Display | ![]() |
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PDB format | ![]() | 110.1 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Summary document | ![]() | 1.5 MB | Display | ![]() |
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Full document | ![]() | 1.5 MB | Display | |
Data in XML | ![]() | 44 KB | Display | |
Data in CIF | ![]() | 61.9 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 15233MC ![]() 5etcC ![]() 5etiC M: map data used to model this data C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
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Assembly
Deposited unit | ![]()
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Components
#1: Protein | Mass: 43647.727 Da / Num. of mol.: 1 / Mutation: T180V Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() References: UniProt: Q16539, mitogen-activated protein kinase | ||||
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#2: Protein | Mass: 41822.844 Da / Num. of mol.: 1 / Mutation: S207D, T211D Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() References: UniProt: P52564, mitogen-activated protein kinase kinase | ||||
#3: Chemical | #4: Chemical | ChemComp-MG / Has ligand of interest | Y | |
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
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Sample preparation
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Molecular weight | Value: 0.0802 MDa / Experimental value: YES | ||||||||||||||||||||||||
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Buffer solution | pH: 7.5 | ||||||||||||||||||||||||
Buffer component |
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Specimen | Conc.: 0.48 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES | ||||||||||||||||||||||||
Specimen support | Grid material: GOLD / Grid type: UltrAuFoil R1.2/1.3 | ||||||||||||||||||||||||
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 298 K / Details: blot for 3.5 seconds |
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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: ![]() |
Electron lens | Mode: BRIGHT FIELD / Nominal magnification: 215000 X / Nominal defocus max: 3000 nm / Nominal defocus min: 1500 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm |
Specimen holder | Cryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Temperature (max): 70 K / Temperature (min): 70 K |
Image recording | Electron dose: 62.77 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 QUANTUM (4k x 4k) / Num. of grids imaged: 3 / Num. of real images: 28633 |
Image scans | Movie frames/image: 40 |
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Processing
Software | Name: PHENIX / Version: 1.20.1_4487: / Classification: refinement | |||||||||||||||||||||||||||||||||||||||||||||
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EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | |||||||||||||||||||||||||||||||||||||||||||||
3D reconstruction | Resolution: 4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 35123 / Symmetry type: POINT | |||||||||||||||||||||||||||||||||||||||||||||
Atomic model building | Protocol: RIGID BODY FIT / Space: REAL | |||||||||||||||||||||||||||||||||||||||||||||
Atomic model building |
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