Crystal Structures of Intact IgG Antibodies

Abstract

Crystal structures of intact IgG immunoglobulins have provided new insight into the interrelations of the Fab arms responsible for antigen binding and the Fc region mediating effector functions such as complement fixation and receptor attachment. Human immunoglobulins lacking the "hinge" region critical for segmental flexibility between the Fabs and the Fc (e.g., Dob and Mcg IgG1 proteins) exhibit Fc units that are represented by interpretable modules of electron density. In contrast, two human "cryoglobulins" (Kol IgG1 and Zie IgG2 molecules) with normal hinge regions have mobile Fc units that do not contribute to the X-ray diffraction patterns. A murine IgG2a antibody (Mab 231) has longer and less restricted Fab-Fc connectors, which act more like flexible tethers than hinges. These tethers permit movements of the Fc into crystal packing arrangements in which they are secured in a single orientation. The ensuing order gives rise to well-defined electron density for the Fc. In the process the inherent symmetry between the two halves of the molecule is lost. Half molecules are related by a crystallographic twofold axis of rotation in each of the human crystalline immunoglobulins. All crystals show some disorder, but the Kol, Mcg, and Mab 231 have been solved to sufficiently high resolution (3.1 to3.5 Å) to trace the polypeptide chains and correlate structural and functional relationships in considerable detail.