9YOR

Cryo-EM structure of a preformed dimer of the C. elegans EGFR (LET-23) extracellular region

Summary for 9YOR

• Entry DOI: 10.2210/pdb9yor/pdb
• EMDB information: 73275 73276 73277 73278 73279
• Descriptor: Receptor tyrosine-protein kinase let-23, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• Functional Keywords: receptor tyrosine kinase, epidermal growth factor receptor, preformed dimer, let-23, signaling protein
• Biological source: Caenorhabditis elegans
• Total number of polymer chains: 2
• Total formula weight: 187793.71

Authors

Zuo, Y.,Han, L.,Ferguson, K.M. (deposition date: 2025-10-13, release date: 2026-07-29, Last modification date: 2026-08-05)

Primary citation

Zuo, Y.,Schwartz, H.T.,Walker, K.,Han, L.,Sternberg, P.W.,Ferguson, K.M.
Ligand regulation and function of preformed EGFR dimers.
Proc.Natl.Acad.Sci.USA, 123:e2602436123-e2602436123, 2026

PubMed 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 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.

PubMed: 42475585
DOI: 10.1073/pnas.2602436123

Experimental method

ELECTRON MICROSCOPY (2.9 Å)