FIGURE 6.

Key interactions of TBG in regulating hormone binding and release. Hormone binding and release involves coherent movements of three closely associated elements: the connecting loops of hDs2A (dashed black line), s2/3B (thin red line), and s4/5B (thick red line). Thus, the binding of thyroxine will be destabilized by slight changes within any of these elements including increases in the flexibility of the hDs2A loop in the S-to-R transition, removal of residues from the top of hD, loosening the packing between hD and s2/3A by the K243G mutation, or the removal the side chain of Arg³⁷⁸. Replacing the homologous residue 243 in CBG, a glycine, with a bulkier valine will similarly affect the packing and also lead to decreased hormone binding affinity (28). Also, only the ligands that are fitted perfectly in the hormone-binding site and form direct interactions with Arg³⁷⁸ can be efficiently released following the S-to-R transitions of TBG.