Antigen-binding loops

The surfaces of the receptors that bind to the topographically different Sitel and Site2 binding sites on the hormones are formed by six closely spaced surface loops (L1-L6) that extend from the /3-sheet core in a manner somewhat similar to antigen binding loops in antibodies. Three loops reside in the N-terminal domain (L1-L3) two others in the G-terminal domain (L5-L6). Binding loop L4 serves as the five residue... 

A. Tramontano and A. M. Lesk. Common features of the conformations of antigen binding loops in immunoglobulins and application to modeling loop conformations. Proteins 73 231-245 (1992). 

For both of the reported anti-IgE antibodies, the process of humanization was utilized to make them therapeutically acceptable. Humanized antibodies significantly reduce the amount of nonhuman sequence in the molecule and have been shown to reduce the occurrence of anti-antibody response when used clinically (73). This technique, pioneered by Winter and colleagues (74-76), involves transplantation of the nonhuman antigen-binding loops (also referred to as complementarity-determining regions, or CDRs) onto a human antibody framework. In addition to CDRs, select nonhuman framework residues may also be incorporated into the humanized antibody in order to maintain proper CDR conformation (77) or because they interact directly with the antigen (78). The humanized antibody, when properly constmcted, contains approximately 5-8% nonhuman residues, the majority of which will be in the CDRs. Several humanized antibodies are now successful therapeutics (79-81), and many more are currently in clinical trials (see Chap. 20). 

The variable domains associate in a strikingly different manner. It is obvious from Figure 15.11 that if they were associated in the same way as the constant domains, via the four-stranded p sheets, the CDR loops, which are linked mainly to the five-stranded p sheet, would be too far apart on the outside of each domain to contribute jointly to the antigen-binding site. Thus in the variable domains the five-stranded p sheets form the domain-domain interaction area (Figure 15.11). Furthermore, the relative orientation of the p strands in the two domains is closer to parallel than in the constant domains and the curvature of the five-stranded p sheets is such that they do not pack... 

Tig. 11.10. Z-score distribution for two randomized regions of an Fd fragment (PDB file laqk, chain H). White bars residues 100, 104—106 (part of antigen binding region), black bars residues 153, 180, 182, 184 (in loop of C-terminal half of the chain). The arrow marks the z-score of tire wild type. 

Amine 2 was coupled to the tetraacid chloride derivative of 1 ( COCl)2, DMF) and depro-tected with trifluoroacetic acid (TFA) to give the tetraloop structure 3. The molecular structure of this host (Fig [13.]1) resembles that of the antigen binding region of an antibody but is based on four loops rather than six. (p. 2681)... 

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