STRUCTURAL STUDIES OF HUMAN AUTOANTIBODIES - CRYSTAL-STRUCTURE OF A THYROID PEROXIDASE AUTOANTIBODY FAB

The three-dimensional structure of the Fab of TR1.9, a high-affinity I gG1,kappa human autoantibody to thyroid peroxidase, was determined cry stallographically to a resolution of 2.0 Angstrom. The combining site was found to be relatively flat, like other antibodies to large protei ns, Sequence differences from the most closely related germline genes mainly occur at positions occupied by residues with outward-pointing s ide chains. An increased deformability of the second and third complem entarity determining regions of the heavy chain may result from the re placement of two germline asparagines and the presence of several glyc ines, and may allow ''induced fit'' in the binding to antigen. Four ex posed charged residues, resulting from the use of a particular D (dive rsity) and J (joining) segments in the assembly of the heavy chain, ma y contribute to the high affinity of antigen binding. The crystal stru cture of TR1.9 Fab is the first for a human IgG high-affinity autoanti body.