The crystal structure of the amino-terminal LG domain of SHBG in complex with 5a-dihydrotestosterone at 1.55 Å resolution reveals the structure of the LG domain as such as well as the architecture of the steroid-binding site and the quaternary structure of the dimer. The steroid and a 20 Å distant calcium ion are not located at the dimer interface. Instead, two separate steroid binding pockets and calcium binding sites exist per dimer. The crystal structures of the tetragonal crystal form and the EDTA-soaked trigonal crystals of SHBG completed the original structure and reveal the loop segment that covers the steroid-binding pocket. Thus, a more detailed description of the steroid-binding site topography is obtained. The binding of zinc reorients the side-chain of His136 as observed in the original crystal structure of SHBG and in the zinc- complexed crystal structure. Apparently, this residue causes disorder within the loop structure between Pro130 and Arg135.

The crystal structures of SHBG in complex with different ligands, which are estradiol, 5a-androstane, 3b,17b-diol (17b-DHA), 5a-androstane, 3b,17a-diol (17a-DHA), 2-methoxyestradiol (methoxyestradiol), norgestrel, have also been solved. Different SHBG-steroid complexes revealed that the steroid-binding pocket of SHBG is very adaptable and displays different possibilities to accommodate the ligands. The binding may occur in two ways, in a "forward" mode like DHT and other chemically related androgens or in the "reverse" mode like in estradiol and it metabolite methoxyestradiol. Depending on which ligand is bound, conformational rearrangements of the residues lining the pocket occur. The X-ray structures of SHBG-steroid complexes presented here provide a three-dimensional composite of key molecular features for the binding of androgens and estrogens.