Conformational Changes May Be Induced by Antigen Binding

As more x-ray crystallographic analyses of Fab fragments were completed, it became clear that in some cases binding of antigen induces conformational changes in the antibody, antigen, or both. Formation of the complex between neur-aminidase and anti-neuraminidase is accompanied by a change in the orientation of side chains of both the epitope and the antigen-binding site. This conformational change results in a closer fit between the epitope and the antibody's binding site.

In another example, comparison of an anti-hemagglutinin Fab fragment before and after binding to a hemagglutinin peptide antigen has revealed a visible conformational change in the heavy-chain CDR3 loop and in the accessible surface of the binding site. Another striking example of conformational change has been seen in the complex between an Fab fragment derived from a monoclonal antibody against the HIV protease and the peptide epitope of the protease. As shown in Figure 4-11, there are significant changes in the Fab upon binding. In fact, upon antigen binding, the CDR1 region of the light chain moves as much as 1 A and the heavy chain CDR3 moves 2.7 A. Thus, in addition to variability in the

Antigen Binding Antibody

FIGURE 4-11

Structure of a complex between a peptide derived from HIV protease and an Fab fragment from an anti-protease antibody (left) and comparison of the Fab structure before and after pep-tide binding (right). In the right panel, the red line shows the structure of the Fab fragment before it binds the peptide and the blue

Antigen Binding Chain

line shows its structure when bound. There are significant conformational changes in the CDRs of the Fab on binding the antigen. These are especially pronounced in the light chain CDR1 (L1) and the heavy chain CDR3 (H3). [From J. Lescar et al., 1997, J. Mol. Biol. 267:1207; courtesy of G. Bentley, Institute Pasteur.]

FIGURE 4-11

Structure of a complex between a peptide derived from HIV protease and an Fab fragment from an anti-protease antibody (left) and comparison of the Fab structure before and after pep-tide binding (right). In the right panel, the red line shows the structure of the Fab fragment before it binds the peptide and the blue line shows its structure when bound. There are significant conformational changes in the CDRs of the Fab on binding the antigen. These are especially pronounced in the light chain CDR1 (L1) and the heavy chain CDR3 (H3). [From J. Lescar et al., 1997, J. Mol. Biol. 267:1207; courtesy of G. Bentley, Institute Pasteur.]

length and amino acid composition of the CDR loops, the ability of these loops to significantly change conformation upon antigen binding enables antibodies to assume a shape more effectively complementary to that of their epitopes.

As already indicated, conformational changes following antigen binding need not be limited to the antibody. Although it is not shown in Figure 4-11, the conformation of the protease peptide bound to the Fab shows no structural similarity to the corresponding epitope in the native HIV protease. It has been suggested that the inhibition of protease activity by this anti-HIV protease antibody is a result of its distortion of the enzyme's native conformation.

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