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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

Item Type:Article
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
Creators Name:Avvakumov, G.V. and Grishkovskaya, I. and Muller, Y.A. and Hammond, G.L.
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 Asp65 and an interaction between the methoxy group at C-2 and the amido group of Asn82. Accommodation of the 2-MeOE2 methoxy group causes an outward displacement of residues Ser128-Pro130, which appears to disorder and displace the loop region (Leu131-His136) 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 Asp65 (2-fluoroestradiol) or accommodation of the functional group at C-2 (2-bromoestradiol), rather than an interaction with Asn82. 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 Asn82. Understanding how C-2 derivatives of estradiol interact with SHBG could facilitate the design of biologically active synthetic estrogens.
Keywords:Alanine, Asparagine, Aspartic Acid, Binding Sites, Dihydrotestosterone, Estradiol, Hydrogen Bonding, Molecular Models, Molecular Structure, Protein Binding, Protein Conformation, Sex Hormone-Binding Globulin, Tertiary Protein Structure, Zinc
Source:Journal of Biological Chemistry
ISSN:0021-9258
Publisher:American Society for Biochemistry and Molecular Biology (U.S.A.)
Volume:277
Number:47
Page Range:45219-45225
Date:22 November 2002
Official Publication:https://doi.org/10.1074/jbc.M207762200
PubMed:View item in PubMed

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