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- EMDB-56418: Structure of the MAP2K MEK1 in an inactive conformation in comple... -

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Entry
Database: EMDB / ID: EMD-56418
TitleStructure of the MAP2K MEK1 in an inactive conformation 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: Dual specificity mitogen-activated protein kinase kinase 1,Uncharacterized protein,Dual specificity mitogen-activated protein kinase kinase 1
    • Organelle or cellular component: ERK2
      • Protein or peptide: Mitogen-activated protein kinase 1
  • Ligand: ADENOSINE-5'-DIPHOSPHATE
  • Ligand: MAGNESIUM ION
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 / epithelial cell proliferation involved in lung morphogenesis / positive regulation of endodermal cell differentiation / negative regulation of hypoxia-induced intrinsic apoptotic signaling pathway / regulation of vascular associated smooth muscle contraction / phospho-PLA2 pathway / mitogen-activated protein kinase kinase / Signaling by MAPK mutants / positive regulation of muscle contraction ...symbiont-mediated activation of host MAPK cascade / negative regulation of homotypic cell-cell adhesion / epithelial cell proliferation involved in lung morphogenesis / positive regulation of endodermal cell differentiation / negative regulation of hypoxia-induced intrinsic apoptotic signaling pathway / regulation of vascular associated smooth muscle contraction / phospho-PLA2 pathway / mitogen-activated protein kinase kinase / Signaling by MAPK mutants / positive regulation of muscle contraction / Golgi inheritance / placenta blood vessel development / MAP kinase scaffold activity / RAF-independent MAPK1/3 activation / Suppression of apoptosis / regulation of axon regeneration / cerebellar cortex formation / labyrinthine layer development / Gastrin-CREB signalling pathway via PKC and MAPK / Signaling by Activin / melanosome transport / cytosine metabolic process / cardiac neural crest cell development involved in heart development / interleukin-34-mediated signaling pathway / caveolin-mediated endocytosis / response to epidermal growth factor / Signaling by NODAL / Signaling by MAP2K mutants / RSK activation / ERKs are inactivated / type B pancreatic cell proliferation / Regulation of the apoptosome activity / Golgi Cisternae Pericentriolar Stack Reorganization / positive regulation of macrophage proliferation / central nervous system neuron differentiation / outer ear morphogenesis / vesicle transport along microtubule / positive regulation of Ras protein signal transduction / : / Signaling by LTK in cancer / regulation of Golgi inheritance / positive regulation of peptidyl-threonine phosphorylation / mitogen-activated protein kinase kinase kinase binding / ERBB signaling pathway / labyrinthine layer blood vessel development / mammary gland epithelial cell proliferation / positive regulation of axonogenesis / trachea formation / triglyceride homeostasis / Negative feedback regulation of MAPK pathway / regulation of early endosome to late endosome transport / IFNG signaling activates MAPKs / regulation of stress-activated MAPK cascade / positive regulation of neuroinflammatory response / Frs2-mediated activation / MAPK3 (ERK1) activation / ERBB2-ERBB3 signaling pathway / Activation of the AP-1 family of transcription factors / RUNX2 regulates osteoblast differentiation / response to exogenous dsRNA / ERK/MAPK targets / MAPK1 (ERK2) activation / positive regulation of macrophage chemotaxis / regulation of cytoskeleton organization / face development / endodermal cell differentiation / regulation of neurotransmitter receptor localization to postsynaptic specialization membrane / MAP kinase kinase activity / Bergmann glial cell differentiation / positive regulation of protein serine/threonine kinase activity / Recycling pathway of L1 / lung morphogenesis / thyroid gland development / pseudopodium / positive regulation of telomere maintenance / positive regulation of ATP biosynthetic process / Advanced glycosylation endproduct receptor signaling / Uptake and function of anthrax toxins / MAP kinase activity / regulation of ossification / mitogen-activated protein kinase / Regulation of HSF1-mediated heat shock response / negative regulation of cell differentiation / RHO GTPases Activate NADPH Oxidases / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / RHO GTPases Activate WASPs and WAVEs / protein kinase activator activity / Signal attenuation / Growth hormone receptor signaling / Schwann cell development / response to axon injury / Estrogen-stimulated signaling through PRKCZ / stress-activated MAPK cascade / phosphatase binding / keratinocyte differentiation / neuron projection morphogenesis / ERK1 and ERK2 cascade / NPAS4 regulates expression of target genes / Nuclear events stimulated by ALK signaling in cancer / phosphotyrosine residue binding
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: 2.9 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 11, 2026-
Map releaseFeb 11, 2026-
UpdateFeb 18, 2026-
Current statusFeb 18, 2026Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_56418.png

Downloads & links

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Map

FileDownload / File: emd_56418.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
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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)

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.92 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0669
Minimum - Maximum-0.20678288 - 0.5856031
Average (Standard dev.)0.0006000431 (±0.0128877675)
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_56418_msk_1.map
Projections & Slices
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Additional map: B-factor sharpened map of MEK1DDGRA-T185V

Fileemd_56418_additional_1.map
AnnotationB-factor sharpened map of MEK1DDGRA-T185V
Projections & Slices
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Half map: half map A

Fileemd_56418_half_map_1.map
Annotationhalf map A
Projections & Slices
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Half map: half map B

Fileemd_56418_half_map_2.map
Annotationhalf map B
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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: Dual specificity mitogen-activated protein kinase kinase 1,Uncharacterized protein,Dual specificity mitogen-activated protein kinase kinase 1
    • Organelle or cellular component: ERK2
      • Protein or peptide: Mitogen-activated protein kinase 1
  • Ligand: ADENOSINE-5'-DIPHOSPHATE
  • Ligand: MAGNESIUM ION

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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: #1-#2
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: 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: 1
Details: protein chimera of human MEK1, exchanging native KIM (r3-11) by GRA24 KIM (15 residues). Addition of activating mutations on serines in activation-loop: Ser218Asp, Ser222Asp.,protein chimera ...Details: protein chimera of human MEK1, exchanging native KIM (r3-11) by GRA24 KIM (15 residues). Addition of activating mutations on serines in activation-loop: Ser218Asp, Ser222Asp.,protein chimera of human MEK1, exchanging native KIM (r3-11) by GRA24 KIM (15 residues). Addition of activating mutations on serines in activation-loop: Ser218Asp, Ser222Asp.,protein chimera of human MEK1, exchanging native KIM (r3-11) by GRA24 KIM (15 residues). Addition of activating mutations on serines in activation-loop: Ser218Asp, Ser222Asp.,protein chimera of human MEK1, exchanging native KIM (r3-11) by GRA24 KIM (15 residues). Addition of activating mutations on serines in activation-loop: Ser218Asp, Ser222Asp.,protein chimera of human MEK1, exchanging native KIM (r3-11) by GRA24 KIM (15 residues). Addition of activating mutations on serines in activation-loop: Ser218Asp, Ser222Asp.,protein chimera of human MEK1, exchanging native KIM (r3-11) by GRA24 KIM (15 residues). Addition of activating mutations on serines in activation-loop: Ser218Asp, Ser222Asp.
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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Macromolecule #2: Mitogen-activated protein kinase 1

MacromoleculeName: Mitogen-activated protein kinase 1 / type: protein_or_peptide / ID: 2
Details: ERK2 with point mutation on residue 185 to a 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 #3: ADENOSINE-5'-DIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-DIPHOSPHATE / type: ligand / ID: 3 / Number of copies: 2 / Formula: ADP
Molecular weightTheoretical: 427.201 Da
Chemical component information

ChemComp-ADP:
ADENOSINE-5'-DIPHOSPHATE / ADP, energy-carrying molecule*YM

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Macromolecule #4: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 4 / Number of copies: 1 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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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 / Material: GOLD / Support film - Material: GOLD / Support film - topology: HOLEY / Pretreatment - Type: PLASMA CLEANING / Pretreatment - Time: 180 sec. / Pretreatment - Atmosphere: OTHER
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 correctionSoftware - Name: cryoSPARC (ver. v4.7.0) / Software - details: Patch CTF / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL / In silico model: AlphaFold
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. v4.7.0) / Number images used: 142124
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-9tyg:
Structure of the MAP2K MEK1 in an inactive conformation in complex with its substrate MAPK ERK2

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