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J. Biol. Chem., Vol. 275, Issue 34, 25920-25925, August 25, 2000

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Steroid-binding Specificity of Human Sex Hormone-binding Globulin Is Influenced by Occupancy of a Zinc-binding Site^*

George V. Avvakumov, Yves A. Muller^§, and Geoffrey L. Hammond^¶

From the  Departments of Obstetrics & Gynecology and Pharmacology & Toxicology and Medical Research Council Group in Fetal and Neonatal Health and Development, University of Western Ontario, London, Ontario N6A 4L6, Canada and ^§ Forschungsgruppe Kristallographie, Max-Delbrück-Center for Molecular Medicine, Robert-Roessle-Strasse 10, D-13092 Berlin, Germany

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 17-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.

The atomic coordinates and the structure factors (code 1F5F) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

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