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TitleThe role of kinase domain dimerization in EGFR activation.
Journal, issue, pagesStructure, Vol. 34, Issue 3, Page 426-440.e6, Year 2026
Publish dateMar 5, 2026
AuthorsZaritza O Petrova / Long Han / Yuko Tsutsui / Joshua B Sheetz / Kumar D Ashtekar / Mark A Lemmon /
PubMed AbstractThe epidermal growth factor receptor (EGFR) was among the first receptor tyrosine kinases (RTKs) shown to be activated by ligand-induced dimerization. Structural studies explain how ligand binding ...The epidermal growth factor receptor (EGFR) was among the first receptor tyrosine kinases (RTKs) shown to be activated by ligand-induced dimerization. Structural studies explain how ligand binding induces the dimerization of EGFR's extracellular region. Unlike other RTKs, EGFR's intracellular tyrosine kinase domain (TKD) is activated allosterically in an asymmetric dimer that is observed crystallographically, but not in cryo-EM studies of intact EGFR. Here, we show that this asymmetric TKD dimer forms only transiently - explaining its lack of definition by cryo-EM. By engineering an asymmetric TKD dimer and studying a TKD-duplicated lung cancer EGFR variant, we show that TKD dimerization increases kinase activity by several hundred-fold. We were also able to stabilize and visualize discrete asymmetric EGFR TKD dimers at high resolution using cryo-EM. Our findings argue that oncogenic mutations activate EGFR primarily by promoting TKD dimerization, and suggest that the transient nature of EGFR TKD dimers may allow biased EGFR signaling.
External linksStructure / PubMed:41421344 / PubMed Central
MethodsEM (single particle)
Resolution3.27 Å
Structure data

71423

9p9u

EMDB-71423, PDB-9p9u:
EGFR-KDD with compound2
Method: EM (single particle) / Resolution: 3.27 Å

Chemicals

ChemComp-6JS:
3-(furan-2-yl)-N-[5-(furan-2-yl)-2-methoxyphenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Source
  • homo sapiens (human)
KeywordsONCOPROTEIN / Receptor tyrosine kinases / epidermal growth factor receptor / growth factor signaling / dimerization

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