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7 Antibody combining sites: structure and prediction
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Published:November 1996
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Abstract
Antibodies possess a vast repertoire of specificity and affinity. To understand the molecular basis of antibody function requires a knowledge of the structures of free and antigen-bound antibodies, determined by X-ray crystallography or NMR, or ideally both. Although the number of antibody structures is increasing rapidly—at the time of writing 48 structures have been deposited in the Brookhaven Protein Database (PDB) (1)—the rate of structure determination will never match that of sequence acquisition. Thus, to explore fully the structural variability of antibody combining sites, encoded in immunoglobulin variable region sequences, effective structural prediction methods have become essential. Such models will have increasing utility where the structural effects of point mutations within the antibody combining site need to be assessed, where minimal perturbation strategies for the grafting of complementarity determining regions (CDRs) during the process of ‘humanization’ are required, and even where the residues to be targeted for random mutation in the gene library methods now available (e.g. phage libraries) are selected in a more rational manner on the basis of their likely accessibility to antigen. In time, when the antibody sequence/structure relationship is fully understood, de nova design of antibodies will also become possible (2).
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