Review: Precision medicine and driver mutations: Computational methods, functional assays and conformational principles for interpreting cancer drivers
Fig 7
EGFR dimerization and activation.
(A) Model for ligand-induced homodimerization of EGFR. The inactive EGFR monomer forms a symmetric dimer in the inactive state. Ligand binding to the extracellular domain shifts the population to the active EGFR dimer. (B) EGF or ligand binding causes an extended conformation of the extracellular domain, promoting a conformational rearrangement through the transmembrane to juxtamembrane domains [263, 270]. This results in an asymmetric assembly of the kinase domains. In the cartoons, crystal structures of extracellular domain (PDB code: 5XWD), transmembrane domain (PDB code: 5LV6), and kinase domain (PDB code: 2GS7) were used to model the inactive monomer and symmetric dimer. The active asymmetric dimer model employs crystal structures of extracellular domain (PDB code: 3NJP), transmembrane/juxtamembrane domain (PDB code: 2M20), and kinase domain (PDB code: 2GS6). Spheres in the C-terminal tail represent tyrosine (Y) and phosphorylated tyrosine (pY) residues. The mutant kinase domain cartoon employs crystal structure of kinase domain with T790M/L858R mutant (PDB code: 5EDP). EGFR, epidermal growth factor receptor; PDB, protein data bank.