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Steroid ligands bind human sex hormone-binding globulin in specific orientations and produce distinct changes in protein conformation

Item Type:Article
Title:Steroid ligands bind human sex hormone-binding globulin in specific orientations and produce distinct changes in protein conformation
Creators Name:Grishkovskaya, I. and Avvakumov, G.V. and Hammond, G.L. and Catalano, M.G. and Muller, Y.A.
Abstract:The amino-terminal laminin G-like domain of human sex hormone-binding globulin (SHBG) contains a single high affinity steroid-binding site. Crystal structures of this domain in complex with several different steroid ligands have revealed that estradiol occupies the SHBG steroid-binding site in an opposite orientation when compared with 5{alpha}-dihydrotestosterone or C19 androgen metabolites (5{alpha}-androstan-3{beta},17{beta}-diol and 5{epsilon}{alpha}-androstan-3{beta},17{alpha}-diol) or the synthetic progestin levonorgestrel. Substitution of specific residues within the SHBG steroid-binding site confirmed that Ser42 plays a key role in determining high affinity interactions by hydrogen bonding to functional groups at C3 of the androstanediols and levonorgestrel and the hydroxyl at C17 of estradiol. Among residues participating in the hydrogen bond network with hydroxy groups at C17 of C19 steroids or C3 of estradiol, Asp65 appears to be the most important. The different binding mode of estradiol is associated with a difference in the position/orientation of residues (Leu131 and Lys134) in the loop segment (Leul31-His136) that covers the steroid-binding site as well as others (Leu171-Lys173 and Trp84) on the surface of human SHBG and may provide a basis for ligand-dependent interactions between SHBG and other macromolecules. These new crystal structures have also enabled us to construct a simple space-filling model that can be used to predict the characteristics of novel SHBG ligands.
Keywords:Amino Acid Substitution, Base Sequence, Binding Sites, DNA Primers, Ligands, Molecular Models, Protein Conformation, Sex Hormone-Binding Globulin, Site-Directed Mutagenesis, Steroids, Substrate Specificity, Variation, X-Ray Crystallography
Source:Journal of Biological Chemistry
ISSN:0021-9258
Publisher:American Society for Biochemistry and Molecular Biology (U.S.A.)
Volume:277
Number:35
Page Range:32086-32093
Date:30 August 2002
Official Publication:https://doi.org/10.1074/jbc.M203999200
PubMed:View item in PubMed

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