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Steroid-binding specificity of human sex hormone-binding globulin is influenced by occupancy of a zinc-binding site

Item Type:Article
Title:Steroid-binding specificity of human sex hormone-binding globulin is influenced by occupancy of a zinc-binding site
Creators Name:Avvakumov, G.V. and Muller, Y.A. and Hammond, G.L.
Abstract:One calcium-binding site (site I) and a second poorly defined metal-binding site (site II) have been observed previously within the amino-terminal laminin G-like domain (G domain) of human sex hormone-binding globulin (SHBG). By soaking crystals of this structure in 2.5 mM ZnCl2, site II and a new metal-binding site (site III) were found to bind Zn2+. Site II is located close to the steroid-binding site, and Zn2+ is coordinated by the side chains of His83 and His136 and the carboxylate group of Asp65. In this site, Zn2+ prevents Asp65 from interacting with the steroid 17β-hydroxy group and alters the conformations of His83 and His136, as well as a disordered region over the steroid-binding site. Site III is formed by the side chains of His101 and the carboxylate group of Asp117, and the distance between them (2.7 Å) is increased to 3.7 Å in the presence of Zn2+. The affinity of SHBG for estradiol is reduced in the presence of 0.1-1 mM Zn2+, whereas its affinity for androgens is unchanged, and chemically-related metal ions (Cd2+ and Hg2+) have similar but less pronounced effects. This is not observed when Zn2+ coordination at site II is modified by substituting Gln for His136. An alteration in the steroid-binding specificity of human SHBG by Zn2+ occupancy of site II may be relevant in male reproductive tissues where zinc concentrations are very high.
Keywords:Binding Sites, Molecular Conformation, Molecular Models, Molecular Sequence Data, Protein Conformation, Sex Hormone-Binding Globulin, X-Ray Crystallography, Zinc
Source:Journal of Biological Chemistry
ISSN:0021-9258
Publisher:American Society for Biochemistry and Molecular Biology (U.S.A.)
Volume:275
Number:34
Page Range:25920-25925
Date:25 August 2000
PubMed:View item in PubMed

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