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- PDB-9tyh: Structure of the MAP2K MEK1 in an active conformation in complex ... -

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Basic information

Entry
Database: PDB / ID: 9tyh
TitleStructure of the MAP2K MEK1 in an active conformation in complex with its substrate MAPK ERK2
Components
  • Dual specificity mitogen-activated protein kinase kinase 1,Uncharacterized protein,Dual specificity mitogen-activated protein kinase kinase 1
  • Mitogen-activated protein kinase 1
KeywordsSIGNALING PROTEIN / protein kinases / phosphoryl transfer / MAPK / MAP2K / cancer signaling
Function / homology
Function and homology information


symbiont-mediated activation of host MAPK cascade / negative regulation of homotypic cell-cell adhesion / 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 / Golgi inheritance / MAP kinase scaffold activity / RAF-independent MAPK1/3 activation ...symbiont-mediated activation of host MAPK cascade / negative regulation of homotypic cell-cell adhesion / 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 / Golgi inheritance / MAP kinase scaffold activity / RAF-independent MAPK1/3 activation / Suppression of apoptosis / positive regulation of muscle contraction / 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 / outer ear morphogenesis / response to epidermal growth factor / Signaling by NODAL / Signaling by MAP2K mutants / RSK activation / ERKs are inactivated / Bergmann glial cell differentiation / trachea formation / Regulation of the apoptosome activity / Golgi Cisternae Pericentriolar Stack Reorganization / positive regulation of macrophage proliferation / vesicle transport along microtubule / : / regulation of Golgi inheritance / Signaling by LTK in cancer / mitogen-activated protein kinase kinase kinase binding / labyrinthine layer blood vessel development / mammary gland epithelial cell proliferation / ERBB signaling pathway / positive regulation of peptidyl-threonine phosphorylation / triglyceride homeostasis / regulation of early endosome to late endosome transport / Negative feedback regulation of MAPK pathway / regulation of stress-activated MAPK cascade / IFNG signaling activates MAPKs / positive regulation of neuroinflammatory response / Frs2-mediated activation / face development / MAPK3 (ERK1) activation / Activation of the AP-1 family of transcription factors / thyroid gland development / ERBB2-ERBB3 signaling pathway / response to exogenous dsRNA / ERK/MAPK targets / RUNX2 regulates osteoblast differentiation / regulation of cytoskeleton organization / MAPK1 (ERK2) activation / positive regulation of macrophage chemotaxis / MAP kinase kinase activity / regulation of neurotransmitter receptor localization to postsynaptic specialization membrane / positive regulation of protein serine/threonine kinase activity / Recycling pathway of L1 / pseudopodium / lung morphogenesis / positive regulation of telomere maintenance / positive regulation of ATP biosynthetic process / neuromuscular junction development / MAP kinase activity / regulation of ossification / Advanced glycosylation endproduct receptor signaling / Uptake and function of anthrax toxins / mitogen-activated protein kinase / Regulation of HSF1-mediated heat shock response / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / negative regulation of cell differentiation / response to axon injury / RHO GTPases Activate NADPH Oxidases / Signal attenuation / protein kinase activator activity / RHO GTPases Activate WASPs and WAVEs / Growth hormone receptor signaling / ERK1 and ERK2 cascade / stress-activated MAPK cascade / Schwann cell development / phosphatase binding / Estrogen-stimulated signaling through PRKCZ / NPAS4 regulates expression of target genes / neuron projection morphogenesis / phosphotyrosine residue binding / Nuclear events stimulated by ALK signaling in cancer / ciliary tip / myelination / insulin-like growth factor receptor signaling pathway / 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 / NCAM signaling for neurite out-growth / ESR-mediated signaling / thymus development / positive regulation of autophagy / lipopolysaccharide-mediated signaling pathway
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
ADENOSINE-5'-DIPHOSPHATE / Uncharacterized protein / Mitogen-activated protein kinase 1 / Dual specificity mitogen-activated protein kinase kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Toxoplasma gondii ME49 (eukaryote)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.4 Å
Authorsvon Velsen, J. / Juyoux, P. / Bowler, M.W.
Funding support1items
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, 2026Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 11, 2026Provider: repository / Type: Initial release
Revision 1.0Feb 11, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Feb 11, 2026Data content type: Additional map / Part number: 1 / Data content type: Additional map / Provider: repository / Type: Initial release
Revision 1.0Feb 11, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Feb 11, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Feb 11, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Feb 11, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Feb 11, 2026Data content type: Mask / Part number: 1 / Data content type: Mask / Provider: repository / Type: Initial release
Revision 1.0Feb 11, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Feb 18, 2026Group: Data collection / Database references / Category: citation / em_admin
Item: _citation.pdbx_database_id_PubMed / _citation.title / _em_admin.last_update
Revision 1.1Feb 18, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / Category: citation / em_admin / Data content type: EM metadata / EM metadata / EM metadata
Item: _citation.pdbx_database_id_PubMed / _citation.title / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
B: Mitogen-activated protein kinase 1
A: Dual specificity mitogen-activated protein kinase kinase 1,Uncharacterized protein,Dual specificity mitogen-activated protein kinase kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)87,5614
Polymers86,7072
Non-polymers8542
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Mitogen-activated protein kinase 1 / MAP kinase 1 / MAPK 1 / ERT1 / Extracellular signal-regulated kinase 2 / ERK-2 / MAP kinase isoform ...MAP kinase 1 / MAPK 1 / ERT1 / Extracellular signal-regulated kinase 2 / ERK-2 / MAP kinase isoform p42 / p42-MAPK / Mitogen-activated protein kinase 2 / MAP kinase 2 / MAPK 2


Mass: 41724.977 Da / Num. of mol.: 1 / Mutation: Thr185Val
Source method: isolated from a genetically manipulated source
Details: ERK2 with point mutation on residue 185 to a valine
Source: (gene. exp.) Homo sapiens (human) / Gene: MAPK1, ERK2, PRKM1, PRKM2 / Production host: Escherichia coli (E. coli) / Strain (production host): Rosetta2
References: UniProt: P28482, mitogen-activated protein kinase
#2: Protein Dual specificity mitogen-activated protein kinase kinase 1,Uncharacterized protein,Dual specificity mitogen-activated protein kinase kinase 1 / MAP kinase kinase 1 / MAPKK 1 / MKK1 / ERK activator kinase 1 / MAPK/ERK kinase 1 / MEK 1


Mass: 44981.562 Da / Num. of mol.: 1
Mutation: residue 3-11 replaced with GRA24 KIM (15 residues),Ser218Asp,Ser222Asp
Source method: isolated from a genetically manipulated source
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
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) Toxoplasma gondii ME49 (eukaryote)
Gene: MAP2K1, MEK1, PRKMK1, TGME49_230180 / Cell line (production host): High Five / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: Q02750, UniProt: A0A125YG37, mitogen-activated protein kinase kinase
#3: Chemical ChemComp-ADP / ADENOSINE-5'-DIPHOSPHATE


Mass: 427.201 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H15N5O10P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: ADP, energy-carrying molecule*YM
Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSourceDetails (eV)
1Complex between the MAP2K MEK1 and its substrate MAPK ERK2COMPLEX#1-#20RECOMBINANT
2MEK1DDGRAORGANELLE OR CELLULAR COMPONENT#11RECOMBINANThuman MEK1 with KIM motif exchanged to GRA24 KIM (15 residues).
3ERK2ORGANELLE OR CELLULAR COMPONENT#21RECOMBINANThuman ERK2 with point mutation on T185V.
Molecular weight
IDEntity assembly-IDValue (°)Experimental value
1186.6 kDa/nmNO
2144.9 kDa/nmNO
3141.7 kDa/nmNO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
32Homo sapiens (human)9606
43Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-IDStrain
21Trichoplusia ni (cabbage looper)7111HighFive
32Trichoplusia ni (cabbage looper)7111HighFive
43Escherichia coli (E. coli)562Rosetta2
Buffer solutionpH: 7.5
Buffer component
IDConc.NameFormulaBuffer-ID
150 mMHEPES pH 7.51
2200 mMsodium chlorideNaCl1
310 mMmagnesium chlorideMgCl21
45 %Glycerol1
50.5 mMTCEP1
SpecimenConc.: 0.516 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: 250 uM ADP.AlF4- was added to the sample
Specimen supportGrid material: GOLD / Grid type: HexAuFoil
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 279.15 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 270000 X / Nominal defocus max: 2200 nm / Nominal defocus min: 1000 nm / Cs: 2.7 mm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 1.7 sec. / Electron dose: 50 e/Å2 / Film or detector model: TFS FALCON 4i (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 88517
EM imaging opticsEnergyfilter name: TFS Selectris X / Energyfilter slit width: 10 eV

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Processing

EM software
IDNameVersionCategoryDetails (eV)
1cryoSPARCv4.7.0particle selectionblob picker then Topaz
2PHENIX1.21.2_5419+SVNmodel refinement
5cryoSPARCv4.7.0CTF correctionPatch CTF
13cryoSPARCv4.7.03D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 113564 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT / Space: REAL
Atomic model buildingSource name: AlphaFold / Type: in silico model
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 223.34 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00275229
ELECTRON MICROSCOPYf_angle_d0.67537080
ELECTRON MICROSCOPYf_chiral_restr0.0424777
ELECTRON MICROSCOPYf_plane_restr0.005900
ELECTRON MICROSCOPYf_dihedral_angle_d6.4966713

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