The identification of members of the epidermal growth factor receptor (EGFR) family on cancer cells created a flurry of research to find therapeutic compounds that target the receptors (for example, the monoclonal antibody treatment Herceptin). But the race has also been on to determine the crystal structure of the ligand–receptor complex, to allow new compounds to be discovered on the basis of rational drug design. Now, in Cell, two groups have claimed victory.
Garrett and colleagues looked at the EGFR–transforming growth factor-α (TGF-α) complex, and Yokoyama and colleagues looked at the EGFR–EGF complex. It was known that ligand-mediated EGFR dimerization occurs, but unlike other growth-factor–receptor complexes, the researchers found that the ligand binds exclusively to a single EGFR molecule through specific regions of the EGFR extracellular domain that are outside the dimer interface. Instead of participating directly in the dimerization of receptors, the ligand seems to induce a conformational change in EGFR that allows a 'protruding arm' from each of the two receptors to then mediate dimerization and activation.
The findings have revealed a novel mechanism of receptor dimerization and this understanding of EGFR activation at the three-dimensional structural level could provide a way to rationally design anti-cancer drugs that block signalling through inhibition of dimerization.
References
ORIGINAL RESEARCH PAPER
Garrett, T. P. J. et al. Crystal structure of a truncated epidermal growth factor receptor extracellular domain bound to transforming growth factor-α. Cell 110, 763–773 (2002)
Ogiso, H. et al. Crystal structure of the complex of human epidermal growth factor and receptor extracellular domains. Cell 110, 775–787 (2002)
FURTHER READING
Schlessinger, J. Ligand-induced, receptor-mediated dimerization and activation of EGF receptor. Cell 110, 669–672 (2002)
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Frantz, S. Complex is crystal clear. Nat Rev Drug Discov 1, 842 (2002). https://doi.org/10.1038/nrd952
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DOI: https://doi.org/10.1038/nrd952