A systematic comparison of free and bound antibodies reveals binding-related conformational changes.

To study structural changes that occur in Abs upon Ag binding, we systematically compared free and bound structures of all 141 crystal structures of the 49 Abs that were solved in these two forms. We found that many structural changes occur far from the Ag binding site. Some of them may constitute a mechanism for the recently suggested allosteric effects in Abs. Within the binding site itself, CDR-H3 is the only element that shows significant binding-related conformational changes; however, this occurs in only one third of the Abs. Beyond the binding site, Ag binding is associated with changes in the relative orientation of the H and L chains in both the variable and constant domains. An even larger change occurs in the elbow angle between the variable and the constant domains, and it is significantly larger for binding of big Ags than for binding of small ones. The most consistent and substantial conformational changes occur in a loop in the H chain constant domain. This loop is implicated in the interaction between the H and L chains, is often intrinsically disordered, and is involved in complement binding. Hence, we suggest that it may have a role in Ab function. These findings provide structural insight into the recently proposed allosteric effects in Abs.