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A single antibody was shown to adopt different binding-site conformations and thereby bind unrelated antigens. Analysis by both x-ray crystallography and pre-steady-state kinetics revealed an equilibrium between different preexisting isomers, one of which possessed a promiscuous, low-affinity binding site for aromatic ligands, including the immunizing hapten. A subsequent induced-fit isomerization led to high-affinity complexes with a deep and narrow binding site. A protein antigen identified by repertoire selection made use of an unrelated antibody isomer with a wide, shallow binding site. Conformational diversity, whereby one sequence adopts multiple structures and multiple functions, can increase the effective size of the antibody repertoire but may also lead to autoimmunity and allergy.
Since the identification of antibodies at the end of the 19th century, scientists have sought to explain how a limited repertoire of antibodies can bind and thereby protect against an almost infinite diversity of invading antigens. The discovery of clonal selection revealed that the combinatorial arrangement of a rather small number of different antibody gene segments has the potential to generate a highly diverse repertoire of antibodies. However, the number of antibodies in the primary response is finite, whereas antigen space is effectively limitless. A possible explanation is that each antibody is capable of binding more than one antigen. Such a scenario was envisaged in the 1940s. Pauling proposed that specific binding sites were selected out of an ensemble of preexisting antibody conformations (1). Indeed, antibodies have been shown to cross-react with multiple antigens ever since they were discovered (26). The first immunologists also realized that cross-reactivity, in addition to expanding the antibody repertoire, could result in the immune system turning against the organism it is meant to defend, or in Ehrlich's chilling words, horror autotoxicus (3). Cross-reactivity is now known to play a central role in autoimmunity and allergy (7, 8). The ability to distinguish between invading antigens and self-proteins can be bypassed when antibodies raised against pathogenic antigens promiscuously bind self-antigens or innocuous environmental molecules (9, 10).
Antibodies are renowned for their exquisite specificity, so how can they be both promiscuous and specific? Structures of antibody fragments that have been cocrystallized with different steroid molecules demonstrate that cross-reactivity can be accomplished through shared ligand chemistry or molecular mimicry (11, 12). The D1.3 antibody...