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Figure 3.
Inhibition mechanism of LFA-1 by Efalizumab. (A) Structural
comparison of the Fab/I domain complex, the ICAM-1/I domain
complex, and ICAM-1. The structures of the Fab/I domain complex
and the ICAM-1/I domain complex are superimposed on the basis of
the I domain, and the structures of ICAM-1 are superimposed on
the basis of domain 1 (residues 1–82). The Fab is shown with a
surface representation in the same colors as in Fig. 1A. The I
domain and ICAM-1 are shown with coiled ribbons. The MIDAS is
shown with the position of Zn^2+ by a green ball. The I domain
in the Fab/I domain complex is colored in pink and the I domain
in the ICAM-1/I domain complex in light blue. ICAM-1 in the
ICAM-1/I domain complex (PDB code 1MQ8) is colored in blue
(molecule A) and red (molecule B), ICAM-1 in the unliganded form
(PDB code 1IAM) in silver, and ICAM-1 in the unliganded form
(PDB code 1IC1) in green (molecule A) and magenta (molecule B),
respectively. (B) A schematic diagram showing the inhibition
mechanism of LFA-1 by Efalizumab. Upon ICAM-1 binding to the
α[L] I domain, LFA-1 undergoes conformational changes and thus
transforms the integrin from the inactive, bent conformation to
the active, extended conformation. Binding of Efalizumab to the
LFA-1 α[L] I domain blocks the binding of ICAM-1 via the steric
hindrance between the Fab light chain and the ICAM-1 domain 2
and thus inhibits the activities of LFA-1.
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