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- EMDB-56420: Structure of the MAP2K MEK1 without bound nucleotide in complex w... -

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Basic information

Entry
Database: EMDB / ID: EMD-56420
TitleStructure of the MAP2K MEK1 without bound nucleotide in complex with its substrate MAPK ERK2
Map datarefined map of MEK1DDGRA-ERK2T185V
Sample
  • Complex: Complex between the MAP2K MEK1 and its substrate MAPK ERK2
    • Organelle or cellular component: MEK1DDGRA
      • Protein or peptide: Mitogen-activated protein kinase 1
    • Organelle or cellular component: ERK2
      • Protein or peptide: Dual specificity mitogen-activated protein kinase kinase 1,Uncharacterized protein,Dual specificity mitogen-activated protein kinase kinase 1
Keywordsprotein kinases / phosphoryl transfer / MAPK / MAP2K / cancer signaling / SIGNALING PROTEIN
Function / homology
Function and homology information


symbiont-mediated activation of host MAPK cascade / negative regulation of homotypic cell-cell adhesion / regulation of vascular associated smooth muscle contraction / negative regulation of hypoxia-induced intrinsic apoptotic signaling pathway / phospho-PLA2 pathway / mitogen-activated protein kinase kinase / Signaling by MAPK mutants / melanosome transport / Golgi inheritance / RAF-independent MAPK1/3 activation ...symbiont-mediated activation of host MAPK cascade / negative regulation of homotypic cell-cell adhesion / regulation of vascular associated smooth muscle contraction / negative regulation of hypoxia-induced intrinsic apoptotic signaling pathway / phospho-PLA2 pathway / mitogen-activated protein kinase kinase / Signaling by MAPK mutants / melanosome transport / Golgi inheritance / RAF-independent MAPK1/3 activation / MAP kinase scaffold activity / Suppression of apoptosis / positive regulation of muscle contraction / Gastrin-CREB signalling pathway via PKC and MAPK / Signaling by Activin / cardiac neural crest cell development involved in heart development / cytosine metabolic process / interleukin-34-mediated signaling pathway / caveolin-mediated endocytosis / outer ear morphogenesis / trachea formation / labyrinthine layer blood vessel development / response to epidermal growth factor / Signaling by NODAL / RSK activation / Signaling by MAP2K mutants / ERKs are inactivated / Bergmann glial cell differentiation / lung morphogenesis / Regulation of the apoptosome activity / Golgi Cisternae Pericentriolar Stack Reorganization / positive regulation of macrophage proliferation / vesicle transport along microtubule / : / mammary gland epithelial cell proliferation / regulation of Golgi inheritance / Signaling by LTK in cancer / mitogen-activated protein kinase kinase kinase binding / positive regulation of peptidyl-threonine phosphorylation / face development / ERBB signaling pathway / triglyceride homeostasis / regulation of early endosome to late endosome transport / thyroid gland development / Negative feedback regulation of MAPK pathway / regulation of stress-activated MAPK cascade / positive regulation of neuroinflammatory response / IFNG signaling activates MAPKs / Frs2-mediated activation / response to exogenous dsRNA / Activation of the AP-1 family of transcription factors / MAPK3 (ERK1) activation / ERBB2-ERBB3 signaling pathway / ERK/MAPK targets / RUNX2 regulates osteoblast differentiation / regulation of cytoskeleton organization / positive regulation of macrophage chemotaxis / MAPK1 (ERK2) activation / positive regulation of protein serine/threonine kinase activity / MAP kinase kinase activity / regulation of neurotransmitter receptor localization to postsynaptic specialization membrane / Recycling pathway of L1 / neuromuscular junction development / pseudopodium / positive regulation of ATP biosynthetic process / positive regulation of telomere maintenance / response to axon injury / regulation of ossification / MAP kinase activity / Uptake and function of anthrax toxins / Advanced glycosylation endproduct receptor signaling / mitogen-activated protein kinase / Regulation of HSF1-mediated heat shock response / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / stress-activated MAPK cascade / ERK1 and ERK2 cascade / RHO GTPases Activate NADPH Oxidases / Signal attenuation / negative regulation of cell differentiation / protein kinase activator activity / RHO GTPases Activate WASPs and WAVEs / Growth hormone receptor signaling / Schwann cell development / thymus development / phosphatase binding / Estrogen-stimulated signaling through PRKCZ / myelination / NPAS4 regulates expression of target genes / lipopolysaccharide-mediated signaling pathway / neuron projection morphogenesis / phosphotyrosine residue binding / insulin-like growth factor receptor signaling pathway / ciliary tip / Nuclear events stimulated by ALK signaling in cancer / RNA polymerase II CTD heptapeptide repeat kinase activity / protein serine/threonine/tyrosine kinase activity / Transcriptional and post-translational regulation of MITF-M expression and activity / ESR-mediated signaling / NCAM signaling for neurite out-growth / positive regulation of autophagy
Similarity search - Function
: / Mitogen-activated protein (MAP) kinase, ERK1/2 / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / : / 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 ...: / Mitogen-activated protein (MAP) kinase, ERK1/2 / Mitogen-activated protein (MAP) kinase, conserved site / MAP kinase signature. / : / 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
Similarity search - Domain/homology
Uncharacterized protein / Mitogen-activated protein kinase 1 / Dual specificity mitogen-activated protein kinase kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.6 Å
Authorsvon Velsen J / Juyoux P / Bowler MW
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: bioRxiv / Year: 2026
Title: Molecular basis of mitogen-activated protein kinase ERK2 activation by its upstream kinase MEK1.
Authors: Jill von Velsen / Pauline Juyoux / Nicola Piasentin / Hayden Fisher / Karine Lapouge / Oscar Vadas / Francesco Luigi Gervasio / Matthew W Bowler /
Abstract: The RAS-RAF-MEK-ERK mitogen-activated protein kinase (MAPK) pathway relays extracellular signals into a cellular response and its dysregulation leads to many pathologies, particularly cancer. Here, ...The RAS-RAF-MEK-ERK mitogen-activated protein kinase (MAPK) pathway relays extracellular signals into a cellular response and its dysregulation leads to many pathologies, particularly cancer. Here, we determined cryo-EM structures of the MAP2K MEK1 activating its substrate MAPK ERK2, the final event in the cascade. We define the molecular details of specificity and phosphoryl transfer to the tyrosine of the ERK2 activation loop and examine the mechanism of substrate recognition using solution techniques and molecular dynamics. Binding of the substrate MAPK leads to release of the MAP2K catalytic machinery, explaining the mechanism of many disease-causing mutations, and ERK2 release is not required for nucleotide exchange, suggesting a processive mechanism. Our data advance the understanding of MAPK signalling and provide a starting point for drug development.
History
DepositionJan 19, 2026-
Header (metadata) releaseFeb 25, 2026-
Map releaseFeb 25, 2026-
UpdateFeb 25, 2026-
Current statusFeb 25, 2026Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_56420.png

Downloads & links

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Map

FileDownload / File: emd_56420.map.gz / Format: CCP4 / Size: 40.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationrefined map of MEK1DDGRA-ERK2T185V
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.92 Å/pix.
x 220 pix.
= 202.4 Å		0.92 Å/pix.
x 220 pix.
= 202.4 Å		0.92 Å/pix.
x 220 pix.
= 202.4 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.92 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0627
Minimum - Maximum-0.1975553 - 0.56823945
Average (Standard dev.)0.00011819758 (±0.013836517)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions220220220
Spacing220220220
CellA=B=C: 202.40001 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_56420_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: B-factor sharpened map.

Fileemd_56420_additional_1.map
AnnotationB-factor sharpened map.
Projections & Slices
AxesZYX

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Density Histograms

Histogram

Histogram (log scale)

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Half map: half mask A

Fileemd_56420_half_map_1.map
Annotationhalf mask A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half mask B

Fileemd_56420_half_map_2.map
Annotationhalf mask B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Complex between the MAP2K MEK1 and its substrate MAPK ERK2

EntireName: Complex between the MAP2K MEK1 and its substrate MAPK ERK2
Components
  • Complex: Complex between the MAP2K MEK1 and its substrate MAPK ERK2
    • Organelle or cellular component: MEK1DDGRA
      • Protein or peptide: Mitogen-activated protein kinase 1
    • Organelle or cellular component: ERK2
      • Protein or peptide: Dual specificity mitogen-activated protein kinase kinase 1,Uncharacterized protein,Dual specificity mitogen-activated protein kinase kinase 1

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Supramolecule #1: Complex between the MAP2K MEK1 and its substrate MAPK ERK2

SupramoleculeName: Complex between the MAP2K MEK1 and its substrate MAPK ERK2
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 41.7 kDa/nm

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Supramolecule #2: MEK1DDGRA

SupramoleculeName: MEK1DDGRA / type: organelle_or_cellular_component / ID: 2 / Parent: 1 / Macromolecule list: #1
Details: human MEK1 with KIM motif exchanged to GRA24 KIM (15 residues).
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: ERK2

SupramoleculeName: ERK2 / type: organelle_or_cellular_component / ID: 3 / Parent: 1 / Macromolecule list: #2 / Details: human ERK2 with point mutation on T185V.
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Mitogen-activated protein kinase 1

MacromoleculeName: Mitogen-activated protein kinase 1 / type: protein_or_peptide / ID: 1 / Details: ERK2 with point mutation on residue 185 to valine / Number of copies: 1 / Enantiomer: LEVO / EC number: mitogen-activated protein kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 41.724977 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: QGPMAAAAAA GAGPEMVRGQ VFDVGPRYTN LSYIGEGAYG MVCSAYDNVN KVRVAIKKIS PFEHQTYCQR TLREIKILLR FRHENIIGI NDIIRAPTIE QMKDVYIVQD LMETDLYKLL KTQHLSNDHI CYFLYQILRG LKYIHSANVL HRDLKPSNLL L NTTCDLKI ...String:
QGPMAAAAAA GAGPEMVRGQ VFDVGPRYTN LSYIGEGAYG MVCSAYDNVN KVRVAIKKIS PFEHQTYCQR TLREIKILLR FRHENIIGI NDIIRAPTIE QMKDVYIVQD LMETDLYKLL KTQHLSNDHI CYFLYQILRG LKYIHSANVL HRDLKPSNLL L NTTCDLKI CDFGLARVAD PDHDHTGFLV EYVATRWYRA PEIMLNSKGY TKSIDIWSVG CILAEMLSNR PIFPGKHYLD QL NHILGIL GSPSQEDLNC IINLKARNYL LSLPHKNKVP WNRLFPNADS KALDLLDKML TFNPHKRIEV EQALAHPYLE QYY DPSDEP IAEAPFKFDM ELDDLPKEKL KELIFEETAR FQPGYRS

UniProtKB: Mitogen-activated protein kinase 1

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Macromolecule #2: Dual specificity mitogen-activated protein kinase kinase 1,Unchar...

MacromoleculeName: Dual specificity mitogen-activated protein kinase kinase 1,Uncharacterized protein,Dual specificity mitogen-activated protein kinase kinase 1
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO / EC number: mitogen-activated protein kinase kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 44.981562 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MPLLERRGVS ELPPLYINPA PDGSAVNGTS SAETNLEALQ KKLEELELDE QQRKRLEAFL TQKQKVGELK DDDFEKISEL GAGNGGVVF KVSHKPSGLV MARKLIHLEI KPAIRNQIIR ELQVLHECNS PYIVGFYGAF YSDGEISICM EHMDGGSLDQ V LKKAGRIP ...String:
MPLLERRGVS ELPPLYINPA PDGSAVNGTS SAETNLEALQ KKLEELELDE QQRKRLEAFL TQKQKVGELK DDDFEKISEL GAGNGGVVF KVSHKPSGLV MARKLIHLEI KPAIRNQIIR ELQVLHECNS PYIVGFYGAF YSDGEISICM EHMDGGSLDQ V LKKAGRIP EQILGKVSIA VIKGLTYLRE KHKIMHRDVK PSNILVNSRG EIKLCDFGVS GQLIDDMAND FVGTRSYMSP ER LQGTHYS VQSDIWSMGL SLVEMAVGRY PIPPPDAKEL ELMFGCQVEG DAAETPPRPR TPGRPLSSYG MDSRPPMAIF ELL DYIVNE PPPKLPSGVF SLEFQDFVNK CLIKNPAERA DLKQLMVHAF IKRSDAEEVD FAGWLCSTIG LNQPSTPTHA AGVL EVLFQ

UniProtKB: Dual specificity mitogen-activated protein kinase kinase 1, Uncharacterized protein, Dual specificity mitogen-activated protein kinase kinase 1

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.516 mg/mL
BufferpH: 7.5
Component:
ConcentrationNameFormula
50.0 mMHEPES pH 7.5
200.0 mMsodium chlorideNaCl
10.0 mMmagnesium chlorideMgCl2
5.0 %Glycerol
0.5 mMTCEP
GridModel: HexAuFoil / Support film - Material: GOLD / Support film - topology: HOLEY
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 279.15 K / Instrument: FEI VITROBOT MARK IV
Details250 uM ADP.AlF4- was added to the sample

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Electron microscopy

MicroscopeTFS KRIOS
Specialist opticsEnergy filter - Name: TFS Selectris X / Energy filter - Slit width: 10 eV
Image recordingFilm or detector model: TFS FALCON 4i (4k x 4k) / Number grids imaged: 1 / Number real images: 88517 / Average exposure time: 1.7 sec. / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.2 µm / Nominal defocus min: 1.0 µm / Nominal magnification: 270000
Sample stageSpecimen 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

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL / In silico model: AlphaFold
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 93925
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelChain - Source name: AlphaFold / Chain - Initial model type: in silico model
RefinementSpace: REAL / Protocol: RIGID BODY FIT
Output model

PDB-9tyi:
Structure of the MAP2K MEK1 without bound nucleotide in complex with its substrate MAPK ERK2

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