title: Crystal structure of human sex hormone-binding globulin in complex with 2-methoxyestradiol reveals the molecular basis for high affinity interactions with C-2 derivatives of estradiol.
abstract: In a crystal structure of the amino-terminal laminin G-like domain of human sex hormone-binding globulin (SHBG), the biologically active estrogen metabolite, 2-methoxyestradiol (2-MeOE2), binds in the same orientation as estradiol. The high affinity of SHBG for 2-MeOE2 relies primarily on hydrogen bonding between the hydroxyl at C-3 of 2-MeOE2 and Asp(65) and an interaction between the methoxy group at C-2 and the amido group of Asn(82). Accommodation of the 2-MeOE2 methoxy group causes an outward displacement of residues Ser(128)-Pro(130), which appears to disorder and displace the loop region (Leu(131)-His(136)) that covers the steroid-binding site. This could influence the binding kinetics of 2-MeOE2 and/or facilitate ligand-dependent interactions between SHBG and other proteins. Occupancy of a zinc-binding site reduces the affinity of SHBG for 2-MeOE2 and estradiol in the same way. The higher affinity of SHBG for estradiol derivatives with a halogen atom at C-2 is due to either enhanced hydrogen bonding between the hydroxyl at C-3 and Asp(65) (2-fluoroestradiol) or accommodation of the functional group at C-2 (2-bromoestradiol), rather than an interaction with Asn(82). By contrast, the low affinity of SHBG for 2-hydroxyestradiol can be attributed to intra-molecular hydrogen bonding between the hydroxyls in the aromatic steroid ring A, which generates a steric clash with the amido group of Asn(82). Understanding how C-2 derivatives of estradiol interact with SHBG could facilitate the design of biologically active synthetic estrogens.
authors.affiliation: Department of Obstetrics & Gynecology and Pharmacology, the Canadian Institutes of Health Research Group in Fetal and Neonatal Health and Development, the University of Western Ontario, London, Ontario N6A 4L6, Canada.
authors.forename: George V
authors.initials: GV
authors.lastname: Avvakumov
authors.forename: Irina
authors.initials: I
authors.lastname: Grishkovskaya
authors.forename: Yves A
authors.initials: YA
authors.lastname: Muller
authors.forename: Geoffrey L
authors.initials: GL
authors.lastname: Hammond
mesh_terms: D000077584:2-Methoxyestradiol; D000409:Alanine / Q000378:metabolism; D001216:Asparagine / Q000378:metabolism; D001224:Aspartic Acid / Q000378:metabolism; D001665:Binding Sites; D013196:Dihydrotestosterone / Q000378:metabolism; D004958:Estradiol / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D012738:Sex Hormone-Binding Globulin / Q000737:chemistry* / Q000378:metabolism; D015032:Zinc / Q000378:metabolism
chemical_list: D012738:Sex Hormone-Binding Globulin; D013196:Dihydrotestosterone; D001224:Aspartic Acid; D004958:Estradiol; D000077584:2-Methoxyestradiol; D001216:Asparagine; D015032:Zinc; D000409:Alanine