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- PDB-9yot: Cryo-EM structure of an inactive dimer of the C. elegans EGFR (LE... -

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Entry
Database: PDB / ID: 9yot
TitleCryo-EM structure of an inactive dimer of the C. elegans EGFR (LET-23) extracellular region bound to LIN-3.
Components
  • Protein spitz,Protein lin-3,Protein lin-3
  • Receptor tyrosine-protein kinase let-23
KeywordsSIGNALING PROTEIN / Receptor Tyrosine Kinase / epidermal growth factor receptor / ligand-bound dimer
Function / homology
Function and homology information


inductive cell-cell signaling / vulval cell fate specification / SHC1 events in ERBB2 signaling / Nuclear signaling by ERBB4 / Signaling by EGFR / GAB1 signalosome / EGFR interacts with phospholipase C-gamma / Sema4D induced cell migration and growth-cone collapse / ERBB2 Regulates Cell Motility / ERBB2 Activates PTK6 Signaling ...inductive cell-cell signaling / vulval cell fate specification / SHC1 events in ERBB2 signaling / Nuclear signaling by ERBB4 / Signaling by EGFR / GAB1 signalosome / EGFR interacts with phospholipase C-gamma / Sema4D induced cell migration and growth-cone collapse / ERBB2 Regulates Cell Motility / ERBB2 Activates PTK6 Signaling / Signaling by ERBB2 / Extra-nuclear estrogen signaling / Drug-mediated inhibition of ERBB2 signaling / Signal transduction by L1 / positive regulation of vulval development / Downregulation of ERBB4 signaling / PIP3 activates AKT signaling / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / PI3K events in ERBB2 signaling / EGFR Transactivation by Gastrin / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / Downregulation of ERBB2 signaling / RAF/MAP kinase cascade / EGFR downregulation / Cargo recognition for clathrin-mediated endocytosis / Clathrin-mediated endocytosis / vulval development / positive regulation of ovulation / nematode larval development / ovulation / egg-laying behavior / uterus development / male genitalia development / regulation of cell fate specification / sleep / post-embryonic development / epidermal growth factor receptor activity / lateral plasma membrane / transmembrane receptor protein tyrosine kinase activity / positive regulation of epithelial cell proliferation / basal plasma membrane / molecular function activator activity / growth factor activity / receptor protein-tyrosine kinase / epidermal growth factor receptor signaling pathway / cell-cell junction / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / neuron differentiation / basolateral plasma membrane / positive regulation of MAPK cascade / signaling receptor complex / apical plasma membrane / receptor ligand activity / lipid binding / negative regulation of apoptotic process / regulation of DNA-templated transcription / : / ATP binding / membrane / plasma membrane
Similarity search - Function
Growth factor receptor domain 4 / Growth factor receptor domain IV / Receptor L-domain / Furin-like cysteine-rich domain / Receptor L-domain superfamily / Furin-like cysteine rich region / Receptor L domain / Furin-like repeat / Furin-like repeats / Epidermal growth factor-like domain. ...Growth factor receptor domain 4 / Growth factor receptor domain IV / Receptor L-domain / Furin-like cysteine-rich domain / Receptor L-domain superfamily / Furin-like cysteine rich region / Receptor L domain / Furin-like repeat / Furin-like repeats / Epidermal growth factor-like domain. / EGF-like domain profile. / Growth factor receptor cysteine-rich domain superfamily / EGF-like domain signature 1. / EGF-like domain signature 2. / EGF-like domain / : / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, 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
Receptor tyrosine-protein kinase let-23 / Protein lin-3
Similarity search - Component
Biological speciesCaenorhabditis elegans (invertebrata)
Drosophila melanogaster (fruit fly)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.81 Å
AuthorsZuo, Y. / Han, L. / Ferguson, K.M.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM149406 United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2026
Title: Ligand regulation and function of preformed EGFR dimers.
Authors: Yuhong Zuo / Hillel T Schwartz / Kahlil Walker / Long Han / Paul W Sternberg / Kathryn M Ferguson /
Abstract: Receptor tyrosine kinases (RTKs) are key therapeutic targets in cancer, diabetes, and other diseases. With only one transmembrane α-helix-compared with seven in G-protein-coupled receptors-RTKs are ...Receptor tyrosine kinases (RTKs) are key therapeutic targets in cancer, diabetes, and other diseases. With only one transmembrane α-helix-compared with seven in G-protein-coupled receptors-RTKs are thought to be activated by ligand-induced dimerization. Complicating this view, however, one of the best-studied RTKs, the insulin receptor (IR), forms allosterically regulated covalent dimers. Moreover, noncovalent "preformed" dimers have frequently been reported for the sequence-related epidermal growth factor receptor (EGFR), one of the first RTKs for which ligand-induced dimerization was described. Here, we describe a detailed structural view of a preformed EGFR dimer. Using cryo-EM, we describe how the EGFR (LET-23) dimerizes without ligand. We show that preformed dimer formation modulates ligand sensitivity in vivo, but is not required for signaling itself. We also elucidate substantial ligand-induced conformational changes in LET-23 required for signaling. Our structures reveal unexpected similarities between regulation of LET-23 and the IR, suggesting that LET-23 may represent an evolutionary "missing link" between the IR and EGFR families. In the absence of ligand, intermolecular interactions within preformed receptor dimers hold the extracellular juxtamembrane regions far apart to separate the intracellular kinase domains so that they remain inactive. Ligand binding disrupts these interactions to remove the restraints on the kinase domains, which then can associate to become activated. Our analysis further suggests a unified model for the allosteric activation of preformed RTK dimers that has important implications for understanding cell-surface EGFR.
History
DepositionOct 13, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 29, 2026Provider: repository / Type: Initial release
Revision 1.0Jul 29, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jul 29, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Jul 29, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
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Revision 1.0Jul 29, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jul 29, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Aug 5, 2026Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Revision 1.1Aug 5, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / EM metadata / Category: citation / citation_author / em_admin
Data content type: EM metadata / EM metadata ...EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Receptor tyrosine-protein kinase let-23
C: Protein spitz,Protein lin-3,Protein lin-3
B: Receptor tyrosine-protein kinase let-23
D: Protein spitz,Protein lin-3,Protein lin-3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)212,12318
Polymers205,6974
Non-polymers6,42614
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

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Protein , 2 types, 4 molecules ABCD

#1: Protein Receptor tyrosine-protein kinase let-23 / Lethal protein 23


Mass: 91067.219 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: Extracellular region (aa 27-819) of C. elegans EGFR, LET-23, with a C-terminal 6x-His tag
Source: (gene. exp.) Caenorhabditis elegans (invertebrata) / Gene: let-23, kin-7, ZK1067.1 / Plasmid: pFastBac / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P24348, receptor protein-tyrosine kinase
#2: Protein Protein spitz,Protein lin-3,Protein lin-3 / Abnormal cell lineage protein 3 / Lethal protein 94


Mass: 11781.285 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: The EGF domain of LIN-3 (aa K148-N206) follows an N-terminal fusion comprising (i) an Arg, (ii) 6xHis tag (iii) aa 44-79 of Drosophila melanogaster SPITZ (Q01083) and (iv) a Factor Xa ...Details: The EGF domain of LIN-3 (aa K148-N206) follows an N-terminal fusion comprising (i) an Arg, (ii) 6xHis tag (iii) aa 44-79 of Drosophila melanogaster SPITZ (Q01083) and (iv) a Factor Xa cleavage site (IEDGR). See PMID 26060020.,The EGF domain of LIN-3 (aa K148-N206) follows an N-terminal fusion comprising (i) an Arg, (ii) 6xHis tag (iii) aa 44-79 of Drosophila melanogaster SPITZ (Q01083) and (iv) a Factor Xa cleavage site (IEDGR). See PMID 26060020.
Source: (gene. exp.) Drosophila melanogaster (fruit fly), (gene. exp.) Caenorhabditis elegans (invertebrata)
Gene: spi, CG10334, lin-3, let-94, F36H1.4 / Plasmid: PMT / Cell line (production host): SCHNEIDER 2(S2) CELLS / Production host: Drosophila melanogaster (fruit fly) / References: UniProt: Q03345

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Sugars , 4 types, 14 molecules

#3: Polysaccharide alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1- ...alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 748.682 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-3DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/3,4,3/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3/a4-b1_b4-c1_c3-d1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{}}}}LINUCSPDB-CARE
#4: Polysaccharide
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#5: Polysaccharide alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1- ...alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 748.682 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-6DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/3,4,3/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3/a4-b1_b4-c1_c6-d1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(6+1)][a-D-Manp]{}}}}LINUCSPDB-CARE
#6: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Details

Has ligand of interestN
Has protein modificationY

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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

ComponentName: Inactive dimer of the C. elegans EGFR (LET-23) extracellular region bound to LIN-3.
Type: COMPLEX
Details: Extracellular region (aa 27-819) of C. elegans EGFR, LET-23, with a C-terminal 6x-His tag bound to the EGF domain of LIN-3 (aa K148-N206), with an N-terminal fusion comprising (i) an Arg, ...Details: Extracellular region (aa 27-819) of C. elegans EGFR, LET-23, with a C-terminal 6x-His tag bound to the EGF domain of LIN-3 (aa K148-N206), with an N-terminal fusion comprising (i) an Arg, (ii) 6xHis tag (iii) aa 44-79 of Drosophila melanogaster SPITZ (Q01083) and (iv) a Factor Xa cleavage site (IEDGR).
Entity ID: #1-#2 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Caenorhabditis elegans (invertebrata)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm) / Strain: Sf9 / Plasmid: pFastBac
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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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 defocus max: 2000 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
12cryoSPARC3D reconstruction
13PHENIX1.21rc1_5127model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.81 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 267599 / Symmetry type: POINT
Atomic model buildingSpace: REAL
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 190.96 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.002913344
ELECTRON MICROSCOPYf_angle_d0.549318014
ELECTRON MICROSCOPYf_chiral_restr0.04692040
ELECTRON MICROSCOPYf_plane_restr0.0032310
ELECTRON MICROSCOPYf_dihedral_angle_d13.3944870

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