Immunoglobulin G (IgG) (IgG)

The hydrophobic cavity of Immunoglobulin G (IgG) refers to conserved structural pockets within the antibody molecule, most notably at the interface of the variable domains (V-domains) and the CH2-CH3 interface of the Fc region. In the context of AL amyloidosis, the V-domain cavity is a critical site for therapeutic intervention; small-molecule kinetic stabilizers bind here to prevent the dissociation of immunoglobulin light chains into toxic, amyloid-forming monomers. Another significant hydrophobic pocket exists in the Fc region, serving as the primary binding site for the neonatal Fc receptor (FcRn), which regulates the long serum half-life of IgG. Targeting this Fc pocket with small molecules or biologics can inhibit the IgG-FcRn interaction, a strategy used to treat autoimmune diseases by promoting the rapid clearance of pathogenic autoantibodies. Additionally, a conserved 'nucleotide-binding site' (NBS) within the Fab region is frequently exploited in biotechnology for the site-specific non-covalent loading of drugs, fluorophores, and other small aromatic ligands.

Other names

IgG hydrophobic cavityIgG hydrophobic pocketNucleotide-binding site (NBS)V-domain interface cavityFc-hydrophobic pocketImmunoglobulin light chain variable domain cavity

Small molecules bind to the hydrophobic cavity at the variable domain (V-domain) interface to kinetically stabilize the native dimer and prevent its dissociation into amyloidogenic monomers, or they bind to the Fc-region hydrophobic pocket to inhibit interactions with the neonatal Fc receptor (FcRn), thereby accelerating the clearance of pathogenic autoantibodies.