|
Figure 7.
Figure 7. Matuzumab and Cetuximab Use Different Mechanisms to
Block Ligand-Induced EGFR Dimerization and Activation
In
the center of the scheme, the ligand-induced sEGFR dimer is
represented, with domain I in red, domain II in green, domain
III in gray with red border, domain IV in gray with green
border, and the ligand (E) in violet. The colors for one
protomer are lightened for contrast. On the left-hand side a
scheme is shown to illustrate the mechanism of inhibition of
ligand-induced dimerization by matuzumab. Fab72000 binds to
domain III of sEGFR and sterically prevents the receptor from
adopting the conformation required for dimerization.
Importantly, Fab72000 blocks the local conformational changes in
domain II that are critical for both high-affinity ligand
binding and dimerization. The inhibition is noncompetitive; the
ligand-binding site on domain III is not blocked. This contrasts
with the mechanism of inhibition previously reported for
cetuximab (Li et al., 2005). FabC225 (right side) is a
competitive inhibitor that blocks the ligand-binding site on
domain III. This is the primary mechanism of inhibition of
ligand-mediated dimerization by cetuximab.
|
