CDRs Bind Antigen

The finding that CDRs are the antigen-binding regions of antibodies has been confirmed directly by high-resolution x-ray crystallography of antigen-antibody complexes. Crys-tallographic analysis has been completed for many Fab fragments of monoclonal antibodies complexed either with

Go to www.whfreeman.com/immunology Antibody Recognition of Antigen

^ Molecular Visualization

VH domain

VH domain

CDR1

CDR2

LiiiLil

CDR3

20 40 60 80

Residue position number

FIGURE 4-9

Variability of amino acid residues in the VL and VH domains of human antibodies with different specificities. Three hypervariable (HV) regions, also called complementarity-determining regions (CDRs), are present in both heavy- and light-chain V domains. As shown in Figure 4-7 (right), the three HV regions in the

CDR1

CDR2

CDR3

I. il ..I I. Il■■!II III 1.1 II. ■■.1 ..II. .1. il II I

iiillll

25 50 75

Residue position number

light-chain V domain are brought into proximity in the folded structure. The same is true of the heavy-chain V domain. [Based on E. A. Kabat et al., 1977, Sequence of Immunoglobulin Chains, U.S. Dept. of Health, Education, and Welfare.]

VH domain

VL domain

large globular protein antigens or with a number of smaller antigens including carbohydrates, nucleic acids, peptides, and small haptens. In addition, complete structures have been obtained for several intact monoclonal antibodies. X-ray diffraction analysis of antibody-antigen complexes has shown that several CDRs may make contact with the antigen, and a number of complexes have been observed in which all six CDRs contact the antigen. In general, more residues in the heavy-chain CDRs appear to contact antigen than in the light-chain CDRs. Thus the VH domain often contributes

FIGURE 4-10

(a) Side view of the three-dimensional structure of the combining site of an angiotensin II — Fab complex. The peptide is in red. The three heavy-chain CDRs (HI, H2, H3) and three light-chain CDRs (L1, L2, L3) are each shown in a different color. All six CDRs contain side chains, shown in yellow, that are within van der

Waals contact of the angiotensin peptide. (b) Side view of the van der Waals surface of contact between angiotensin II and Fab fragment. [From K. C. Garcia et al., 1992, Science 257:502; courtesy of M. Amzel, Johns Hopkins University.]

more to antigen binding than the VL domain. The dominant role of the heavy chain in antigen binding was demonstrated in a study in which a single heavy chain specific for a glyco-protein antigen of the human immunodeficiency virus (HIV) was combined with various light chains of different antigenic specificity. All of the hybrid antibodies bound to the HIV glycoprotein antigen, indicating that the heavy chain alone was sufficient to confer specificity. However, one should not conclude that the light chain is largely irrelevant; in some antibody-antigen reactions, the light chain makes the more important contribution.

The actual shape of the antigen binding site formed by whatever combination of CDRs are used in a particular antibody has been shown to vary dramatically. As pointed out in Chapter 3, contacts between a large globular protein antigen and antibody occur over a broad, often rather flat, undulating face. In the area of contact, protrusions or depressions on the antigen are likely to match complementary depressions or protrusions on the antibody. In the case of the well studied lysozyme/anti-lysozyme system, crystallographic studies have shown that the surface areas of interaction are quite large, ranging from about 650 A2 to more than 900 A2. Within this area, some 15-22 amino acids in the antibody contact the same number of residues in the protein antigen. In contrast, antibodies bind smaller antigens, such as small haptens, in smaller, recessed pockets in which the ligand is buried. This is nicely illustrated by the interaction of the small octapeptide hormone angiotensin II with the binding site of an anti-angiotensin antibody (Figure 4-10).

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Responses

  • guadalupe
    How many cdrs to bind antigen?
    8 years ago
  • Helen
    How many cdrs are present on light and heavy chains?
    8 years ago
  • Tess
    Is a heavy chain important to bind to an antigen?
    8 years ago
  • belba burrowes
    How many cdrs in heavy chain of antibody?
    7 months ago

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