Structural analyses of sex hormone-binding globulin reveal novel ligands and function.
Plasma sex hormone-binding globulin (SHBG) regulates the access of androgens and estrogens to their target tissues and cell types. An SHBG homologue, known as the androgen-binding protein, is expressed in Sertoli cells of many mammalians, but testicular expression of human SHBG is restricted to germ cells. The primary structure of SHBG comprises tandem laminin G-like (LG) domains. The amino-terminal LG-domain includes the steroid-binding site and dimerization interface, and its tertiary structure, resolved in complex with natural and synthetic sex steroids, has revealed unanticipated mechanisms of steroid binding at the atomic level. This LG-domain interacts with fibulin-1D and fibulin-2 in a ligand-specific manner, and this is attributed to the unique way estrogens reside within the steroid-binding site, and the ordering of an otherwise flexible loop structure covering the entrance of the steroid-binding pocket. This mechanism enables estradiol to enhance the sequestration of plasma SHBG by the stroma of some tissues through binding to these extra-cellular matrix-associated proteins. The human SHBG amino-terminal LG-domain also contains several cation-binding sites, and occupancy of a zinc-binding site influences its affinity for estradiol. The complete quaternary structure of SHBG remains unresolved but structural predictions suggest that the carboxy-terminal LG-domains extend laterally from the dimerized amino-terminal LG-domains. The carboxy-terminal LG-domain contains two N-glycosylation sites, but their biological significance remains obscure. Knowledge of the SHBG tertiary structure has helped develop computational techniques based on the use of a "bench-mark data set" of steroid ligands, and created novel drug discovery and toxicology risk assessment platforms.
Avvakumov
George V
GV
Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
Cherkasov
Artem
A
Muller
Yves A
YA
Hammond
Geoffrey L
GL
D000818:Animals; D001665:Binding Sites; D002241:Carbohydrates / Q000737:chemistry; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D012738:Sex Hormone-Binding Globulin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015032:Zinc / Q000737:chemistry
D002241:Carbohydrates; D008024:Ligands; D012738:Sex Hormone-Binding Globulin; D015032:Zinc