J. Immunol. 191, 456–463 (2013)

Several autoimmune diseases manifest as a result of molecular mimicry, where completely unrelated molecules, such as an allergen and a self-peptide, share a common receptor. Methyl α-D-mannopyranoside and a dodecapeptide, DVFYPYPYASGS, can be interchangeably bound by the lectin concanavalin A and a monoclonal antibody 2D10 as well as by polyclonal sera. For concanavalin A, binding of the two ligands occurs at different sites, so the differences in molecular recognition of the two ligands are not attributable to their different structures per se. For 2D10, it has been suggested from thermodynamic and in silico studies that 2D10 uses a flexible binding site that can accommodate both antigens. To test this proposal, Tapryal et al. solved the crystal structures of a single-chain variable fragment of 2D10 in an antigen-free state as well as in complexes with the carbohydrate and dodecapeptide. Surprisingly, they found no overall structural differences in the antibody fragments, suggesting a rigid binding site that does not change upon antigen binding. The authors also found that the carbohydrate bound the antibody primarily through polar interactions, whereas the peptide bound via different polar interactions but also by hydrophobic interactions. Therefore, molecular mimicry arises by neither the chemical nature nor the equivalence of the interactions nor with any role for conformational changes at the antigen-binding site but is achieved via plasticity of the antigen-antibody interactions.