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- EMDB-73278: Cryo-EM structure of a weak dimer of the C. elegans EGFR (LET-23)... -

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Basic information

Entry
Database: EMDB / ID: EMD-73278
TitleCryo-EM structure of a weak dimer of the C. elegans EGFR (LET-23) extracellular region with a domain IV loop deletion
Map data
Sample
  • Complex: Weak dimer of the C. elegans EGFR (LET-23) extracellular region with a domain IV loop deletion
    • Protein or peptide: Receptor tyrosine-protein kinase let-23
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsReceptor Tyrosine Kinase / epidermal growth factor receptor / preformed dimer / SIGNALING PROTEIN
Function / homology
Function and homology information


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 ...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 / nematode larval development / ovulation / uterus development / male genitalia development / sleep / 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 / 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 / negative regulation of apoptotic process / regulation of DNA-templated transcription / lipid binding / ATP binding / 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 / Growth factor receptor cysteine-rich domain superfamily ...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 / Growth factor receptor cysteine-rich domain superfamily / : / 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
Similarity search - Component
Biological speciesCaenorhabditis elegans (invertebrata)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.0 Å
AuthorsZuo Y / Walker K / Han L / Ferguson KM
Funding support United States, 1 items
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, 2025-
Header (metadata) releaseJul 29, 2026-
Map releaseJul 29, 2026-
UpdateAug 5, 2026-
Current statusAug 5, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_73278.png

Downloads & links

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Map

FileDownload / File: emd_73278.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.24 Å/pix.
x 256 pix.
= 316.8 Å		1.24 Å/pix.
x 256 pix.
= 316.8 Å		1.24 Å/pix.
x 256 pix.
= 316.8 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.2375 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.2
Minimum - Maximum-0.17967236 - 0.4308101
Average (Standard dev.)-0.00049742917 (±0.01460571)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 316.8 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_73278_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

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Half map: #1

Fileemd_73278_half_map_2.map
Projections & Slices
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Sample components

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Entire : Weak dimer of the C. elegans EGFR (LET-23) extracellular region w...

EntireName: Weak dimer of the C. elegans EGFR (LET-23) extracellular region with a domain IV loop deletion
Components
  • Complex: Weak dimer of the C. elegans EGFR (LET-23) extracellular region with a domain IV loop deletion
    • Protein or peptide: Receptor tyrosine-protein kinase let-23
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Weak dimer of the C. elegans EGFR (LET-23) extracellular region w...

SupramoleculeName: Weak dimer of the C. elegans EGFR (LET-23) extracellular region with a domain IV loop deletion
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Details: Extracellular region (aa 27-819) of C. elegans EGFR, LET-23, with a C-terminal 6x-His tag and amino acids Y594_M602 have been deleted and a GG inserted (p.Y594_M620insGG).
Source (natural)Organism: Caenorhabditis elegans (invertebrata)

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Macromolecule #1: Receptor tyrosine-protein kinase let-23

MacromoleculeName: Receptor tyrosine-protein kinase let-23 / type: protein_or_peptide / ID: 1
Details: Extracellular region (aa 27-819) of C. elegans EGFR, LET-23, with a C-terminal 6x-His tag and amino acids Y594_M602 have been deleted and a GG inserted (p.Y594_M620insGG)
Number of copies: 2 / Enantiomer: LEVO / EC number: receptor protein-tyrosine kinase
Source (natural)Organism: Caenorhabditis elegans (invertebrata)
Molecular weightTheoretical: 90.095172 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: QLWKRCVSPQ DCLCSGTTNG ISRYGTGNIL EDLETMYRGC RRVYGNLEIT WIEANEIKKW RESTNSTVDP KNEDSPLKSI NFFDNLEEI RGSLIIYRAN IQKISFPRLR VIYGDEVFHD NALYIHKNDK VHEVVMRELR VIRNGSVTIQ DNPKMCYIGD K IDWKELLY ...String:
QLWKRCVSPQ DCLCSGTTNG ISRYGTGNIL EDLETMYRGC RRVYGNLEIT WIEANEIKKW RESTNSTVDP KNEDSPLKSI NFFDNLEEI RGSLIIYRAN IQKISFPRLR VIYGDEVFHD NALYIHKNDK VHEVVMRELR VIRNGSVTIQ DNPKMCYIGD K IDWKELLY DPDVQKVETT NSHQHCYQNG KSMAKCHESC NDKCWGSGDN DCQRVYRSVC PKSCSQCFYS NSTSSYECCD SA CLGGCTG HGPKNCIACS KYELDGICIE TCPSRKIFNH KTGRLVFNPD GRYQNGNHCV KECPPELLIE NDVCVRHCSD GHH YDATKD VRECEKCRSS SCPKICTVDG HLTNETLKNL EGCEQIDGHL IIEHAFTYEQ LKVLETVKIV SEYITIVQQN FYDL KFLKN LQIIEGRKLH NVRWALAIYQ CDDLEELSLN SLKLIKTGAV LIMKNHRLCY VSKIDWSSII TSKGKDNKPS LAIAE NRDS KLCETEQRVC DKNCNKRGCW GKEPEDCLEC KTWKSVGTCV EKCDTKGFLR NQTSMKCERC SPECETCNGL GELDCL TCR HKTLGGECVH DCPVSHFPTQ KNVCEKCHPT CYDNGCTGPD SNLGYGGCKQ CKYAVKYEND TIFCLQSSGM NNVCVEN DL PNYYISTYDT EGVIETHCEK CSISCKTCSS AGRNVVQNKC VCKHVEYQPN PSERICMDQC PVNSFMVPDT NNTVCKKC H HECDQNYHCA NGQSTGCQKC KNFTVFKGDI AQCVSECPKN LPFSNPANGE CLDYDIASRQ RKTRMHHHHH H

UniProtKB: Receptor tyrosine-protein kinase let-23, Receptor tyrosine-protein kinase let-23

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Macromolecule #5: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 5 / Number of copies: 2 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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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

Concentration5 mg/mL
BufferpH: 7.4
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 289 K

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / 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 / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.8 µm
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
Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.0 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 155789
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: AB INITIO MODEL
Output model

PDB-9you:
Cryo-EM structure of a weak dimer of the C. elegans EGFR (LET-23) extracellular region with a domain IV loop deletion

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