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- PDB-9tyi: Structure of the MAP2K MEK1 without bound nucleotide in complex w... -

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Basic information

Entry
Database: PDB / ID: 9tyi
TitleStructure of the MAP2K MEK1 without bound nucleotide 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 / 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 / Suppression of apoptosis / MAP kinase scaffold activity / Gastrin-CREB signalling pathway via PKC and MAPK / positive regulation of muscle contraction / Signaling by Activin / interleukin-34-mediated signaling pathway / caveolin-mediated endocytosis / Signaling by NODAL / RSK activation / ERKs are inactivated / Signaling by MAP2K mutants / response to epidermal growth factor / vesicle transport along microtubule / Regulation of the apoptosome activity / Golgi Cisternae Pericentriolar Stack Reorganization / positive regulation of macrophage proliferation / positive regulation of skeletal muscle tissue regeneration / Signaling by LTK in cancer / regulation of Golgi inheritance / mitogen-activated protein kinase kinase kinase binding / positive regulation of peptidyl-threonine phosphorylation / ERBB signaling pathway / positive regulation of protein serine/threonine kinase activity / triglyceride homeostasis / Negative feedback regulation of MAPK pathway / regulation of early endosome to late endosome transport / regulation of stress-activated MAPK cascade / IFNG signaling activates MAPKs / positive regulation of neuroinflammatory response / Frs2-mediated activation / Activation of the AP-1 family of transcription factors / MAPK3 (ERK1) activation / ERK/MAPK targets / ERBB2-ERBB3 signaling pathway / RUNX2 regulates osteoblast differentiation / MAPK1 (ERK2) activation / positive regulation of macrophage chemotaxis / regulation of cytoskeleton organization / regulation of neurotransmitter receptor localization to postsynaptic specialization membrane / MAP kinase kinase activity / Recycling pathway of L1 / response to axon injury / pseudopodium / positive regulation of ATP biosynthetic process / MAP kinase activity / neuromuscular junction development / positive regulation of telomere maintenance / ERK1 and ERK2 cascade / Advanced glycosylation endproduct receptor signaling / Uptake and function of anthrax toxins / positive regulation of smoothened signaling pathway / mitogen-activated protein kinase / Regulation of HSF1-mediated heat shock response / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / stress-activated MAPK cascade / RHO GTPases Activate NADPH Oxidases / Signal attenuation / protein kinase activator activity / Growth hormone receptor signaling / RHO GTPases Activate WASPs and WAVEs / Schwann cell development / phosphatase binding / Estrogen-stimulated signaling through PRKCZ / ciliary tip / myelination / insulin-like growth factor receptor signaling pathway / NPAS4 regulates expression of target genes / phosphotyrosine residue binding / neuron projection morphogenesis / Nuclear events stimulated by ALK signaling in cancer / protein serine/threonine/tyrosine kinase activity / Transcriptional and post-translational regulation of MITF-M expression and activity / RNA polymerase II CTD heptapeptide repeat kinase activity / ESR-mediated signaling / positive regulation of autophagy / NCAM signaling for neurite out-growth / response to glucocorticoid / protein serine/threonine kinase activator activity / dendrite cytoplasm / cellular response to amino acid starvation / Regulation of PTEN gene transcription / Signal transduction by L1 / response to nicotine / chemokine-mediated signaling pathway / MAP3K8 (TPL2)-dependent MAPK1/3 activation / FCGR3A-mediated phagocytosis / FCERI mediated MAPK activation / positive regulation of transcription elongation by RNA polymerase II / Negative regulation of FGFR3 signaling / Negative regulation of FGFR2 signaling
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)
Toxoplasma gondii ME49 (eukaryote)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.6 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 25, 2026Provider: repository / Type: Initial release
Revision 1.0Feb 25, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Feb 25, 2026Data content type: Additional map / Part number: 1 / Data content type: Additional map / Provider: repository / Type: Initial release
Revision 1.0Feb 25, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Feb 25, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Feb 25, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Feb 25, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Feb 25, 2026Data content type: Mask / Part number: 1 / Data content type: Mask / Provider: repository / Type: Initial release
Revision 1.0Feb 25, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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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


Theoretical massNumber of molelcules
Total (without water)86,7072
Polymers86,7072
Non-polymers00
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 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
Source method: isolated from a genetically manipulated source
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
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 ERK2COMPLEXall0RECOMBINANT
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 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
IDNameVersionCategory
1cryoSPARCparticle selection
2PHENIX1.21.2_5419model refinement
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 93925 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT / Space: REAL
Atomic model buildingSource name: AlphaFold / Type: in silico model
RefinementHighest resolution: 3.6 Å / Cross valid method: NONE
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0025085
ELECTRON MICROSCOPYf_angle_d0.6156877
ELECTRON MICROSCOPYf_dihedral_angle_d5.077676
ELECTRON MICROSCOPYf_chiral_restr0.042760
ELECTRON MICROSCOPYf_plane_restr0.004880

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