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- EMDB-15233: Structure of the MAPK p38alpha in complex with its activating MAP... -
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Open data
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Basic information
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Title | Structure of the MAPK p38alpha in complex with its activating MAP2K MKK6 | |||||||||
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![]() | Kinase / Signalling / MAP kinase / phosphoryl transfer / IMMUNE SYSTEM | |||||||||
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 | single particle reconstruction / cryo EM / Resolution: 4.0 Å | |||||||||
![]() | Bowler MW / Juyoux P / Pellegrini E | |||||||||
Funding support | 1 items
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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 FL / Pellegrini E / Bowler MW | |||||||||
History |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 119.9 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 22.8 KB 22.8 KB | Display Display | ![]() |
FSC (resolution estimation) | ![]() | 13.3 KB | Display | ![]() |
Images | ![]() | 60.3 KB | ||
Masks | ![]() | 244.1 MB | ![]() | |
Others | ![]() ![]() | 226.3 MB 226.3 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Validation report
Summary document | ![]() | 998 KB | Display | ![]() |
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Full document | ![]() | 997.6 KB | Display | |
Data in XML | ![]() | 22.3 KB | Display | |
Data in CIF | ![]() | 28.8 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8a8mMC ![]() 5etcC ![]() 5etiC M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Annotation | unsharpened map | ||||||||||||||||||||||||||||||||||||
Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 0.638 Å | ||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Mask #1
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-Half map: half map A
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-Half map: half map B
File | emd_15233_half_map_2.map | ||||||||||||
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Annotation | half map B | ||||||||||||
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Sample components
-Entire : Complex between the MAP2K MKK6 and its substrate MAPK p38alpha
Entire | Name: Complex between the MAP2K MKK6 and its substrate MAPK p38alpha |
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Components |
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-Supramolecule #1: Complex between the MAP2K MKK6 and its substrate MAPK p38alpha
Supramolecule | Name: Complex between the MAP2K MKK6 and its substrate MAPK p38alpha type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2 |
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Molecular weight | Theoretical: 80.2 KDa |
-Supramolecule #2: Mitogen-activated protein kinase 14 (MAPK p38alpha)
Supramolecule | Name: Mitogen-activated protein kinase 14 (MAPK p38alpha) / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1 |
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Source (natural) | Organism: ![]() |
-Supramolecule #3: Dual specificity mitogen-activated protein kinase kinase 6 (MAP2K...
Supramolecule | Name: Dual specificity mitogen-activated protein kinase kinase 6 (MAP2K MKK6) type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2 |
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Source (natural) | Organism: ![]() |
-Macromolecule #1: Mitogen-activated protein kinase 14
Macromolecule | Name: Mitogen-activated protein kinase 14 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: mitogen-activated protein kinase |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 43.647727 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: MGSSHHHHHH SSGLEVLFQG PMSQERPTFY RQELNKTIWE VPERYQNLSP VGSGAYGSVC AAFDTKTGLR VAVKKLSRPF QSIIHAKRT YRELRLLKHM KHENVIGLLD VFTPARSLEE FNDVYLVTHL MGADLNNIVK CQKLTDDHVQ FLIYQILRGL K YIHSADII ...String: MGSSHHHHHH SSGLEVLFQG PMSQERPTFY RQELNKTIWE VPERYQNLSP VGSGAYGSVC AAFDTKTGLR VAVKKLSRPF QSIIHAKRT YRELRLLKHM KHENVIGLLD VFTPARSLEE FNDVYLVTHL MGADLNNIVK CQKLTDDHVQ FLIYQILRGL K YIHSADII HRDLKPSNLA VNEDCELKIL DFGLARHTDD EMVGYVATRW YRAPEIMLNW MHYNQTVDIW SVGCIMAELL TG RTLFPGT DHIDQLKLIL RLVGTPGAEL LKKISSESAR NYIQSLTQMP KMNFANVFIG ANPLAVDLLE KMLVLDSDKR ITA AQALAH AYFAQYHDPD DEPVADPYDQ SFESRDLLID EWKSLTYDEV ISFVPPPLDQ EEMES UniProtKB: Mitogen-activated protein kinase 14 |
-Macromolecule #2: Dual specificity mitogen-activated protein kinase kinase 6
Macromolecule | Name: Dual specificity mitogen-activated protein kinase kinase 6 type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO / EC number: mitogen-activated protein kinase kinase |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 41.822844 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: MGSQLLERRG VSELPPLYIP KEAFEQPQTS STPPRDLDSK ACISIGNQNF EVKADDLEPI MELGRGAYGV VEKMRHVPSG QIMAVKRIR ATVNSQEQKR LLMDLDISMR TVDCPFTVTF YGALFREGDV WICMELMDTS LDKFYKQVID KGQTIPEDIL G KIAVSIVK ...String: MGSQLLERRG VSELPPLYIP KEAFEQPQTS STPPRDLDSK ACISIGNQNF EVKADDLEPI MELGRGAYGV VEKMRHVPSG QIMAVKRIR ATVNSQEQKR LLMDLDISMR TVDCPFTVTF YGALFREGDV WICMELMDTS LDKFYKQVID KGQTIPEDIL G KIAVSIVK ALEHLHSKLS VIHRDVKPSN VLINALGQVK MCDFGISGYL VDDVAKDIDA GCKPYMAPER INPELNQKGY SV KSDIWSL GITMIELAIL RFPYDSWGTP FQQLKQVVEE PSPQLPADKF SAEFVDFTSQ CLKKNSKERP TYPELMQHPF FTL HESKGT DVASFVKLIL GDLEVLFQGP WSHPQFEKGG GSGGGSGGSA WSHPQFEK UniProtKB: Dual specificity mitogen-activated protein kinase kinase 6 |
-Macromolecule #3: PHOSPHOMETHYLPHOSPHONIC ACID ADENOSYL ESTER
Macromolecule | Name: PHOSPHOMETHYLPHOSPHONIC ACID ADENOSYL ESTER / type: ligand / ID: 3 / Number of copies: 2 / Formula: AP2 |
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Molecular weight | Theoretical: 425.228 Da |
Chemical component information | ![]() ChemComp-A12: |
-Macromolecule #4: MAGNESIUM ION
Macromolecule | Name: MAGNESIUM ION / type: ligand / ID: 4 / Number of copies: 4 / Formula: MG |
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Molecular weight | Theoretical: 24.305 Da |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Concentration | 0.48 mg/mL | ||||||||||||
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Buffer | pH: 7.5 Component:
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Grid | Model: UltrAuFoil R1.2/1.3 / Material: GOLD / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 30 sec. / Pretreatment - Atmosphere: AIR / Pretreatment - Pressure: 101.325 kPa | ||||||||||||
Vitrification | Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 298 K / Instrument: FEI VITROBOT MARK IV / Details: blot for 3.5 seconds. |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Temperature | Min: 70.0 K / Max: 70.0 K |
Image recording | Film or detector model: GATAN K2 QUANTUM (4k x 4k) / Detector mode: COUNTING / Number grids imaged: 3 / Number real images: 28633 / Average electron dose: 62.77 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | C2 aperture diameter: 50.0 µm / Illumination mode: OTHER / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 3.0 µm / Nominal defocus min: 1.5 µm / Nominal magnification: 215000 |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Image processing
-Atomic model buiding 1
Initial model |
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Refinement | Space: REAL / Protocol: RIGID BODY FIT | ||||||||
Output model | ![]() PDB-8a8m: |