9P9U

EGFR-KDD with compound2

Summary for 9P9U

• Entry DOI: 10.2210/pdb9p9u/pdb
• EMDB information: 71423
• Descriptor: Epidermal growth factor receptor, 3-(furan-2-yl)-N-[5-(furan-2-yl)-2-methoxyphenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2 entities in total)
• Functional Keywords: receptor tyrosine kinases, epidermal growth factor receptor, growth factor signaling, dimerization, oncoprotein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 1
• Total formula weight: 77883.86

Authors

Han, L.,Petrova, Z.O.,Lemmon, M.A. (deposition date: 2025-06-24, release date: 2025-11-19, Last modification date: 2026-06-03)

Primary citation

Petrova, Z.O.,Han, L.,Tsutsui, Y.,Sheetz, J.B.,Ashtekar, K.D.,Lemmon, M.A.
The role of kinase domain dimerization in EGFR activation.
Structure, 34:426-440.e6, 2026

PubMed Abstract: 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.

PubMed: 41421344
DOI: 10.1016/j.str.2025.11.017

Experimental method

ELECTRON MICROSCOPY (3.27 Å)