Comparison of the conformations of two intact monoclonal antibodies with hinges.
Structures of two intact monoclonal antibodies were solved by X-ray diffraction analysis revealing, in both cases, the dispositions of all segments, as well as the structures of the hinge polypeptides. An IgG1, whose antigen is the drug phenobarbital, assumed a completely different conformation when compared with an IgG2a specific for canine lymphoma cells. Though neither IgG displays global two-fold symmetry, both maintain two pseudo dyad axes, one relating Fab segments, and the other the halves of the Fc. In both IgGs, the Fc segment is obliquely disposed with respect to the plane of the Fabs, making an angle of 128 degrees in the IgG2a, and 107 degrees in the IgG1. Hinge angles of the IgG1 are notably different at 78 degrees and 123 degrees, and unique as well from IgG2a values of 66 degrees and 113 degrees. Elbow angles within the IgG1 Fabs are the same at 155 degrees, but non-identical in IgG2a where they took on values of 143 degrees and 159 degrees. The IgG2a has an angle of 172 degrees between Fabs so that it exhibits a "distorted T" shape, whereas that angle in the IgG1 is a much more acute 115 degrees producing a "distorted Y". CH2 domains appear, in both antibodies, to be the most independently mobile of the paired IgG domains. This perhaps reflects their importance in modulating effector functions through exposure of binding loci on the CH2, at the CH2-CH3 interface, and on lower hinge polypeptides. Hinges in both antibodies contain disulfide-linked cores bounded by fluid regions above and below, which provide mobility to the Fabs and Fc respectively. The conformations seen in these two structures are undoubtedly only two among many but they illustrate the modes of flexibility inherent to the IgG architecture.
Department of Molecular Biology and Biochemistry, University of California, Irvine, USA.
L J
LJ
Harris
S B
SB
Larson
E
E
Skaletsky
A
A
McPherson
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry*; D004285:Dogs; D006801:Humans; D008958:Models, Molecular; D009363:Neoplasm Proteins / Q000276:immunology*; D009844:Oligosaccharides / Q000737:chemistry; D010634:Phenobarbital / Q000276:immunology*; D011487:Protein Conformation
D000911:Antibodies, Monoclonal; D009363:Neoplasm Proteins; D009844:Oligosaccharides; D010634:Phenobarbital