Abstract
Human sex hormone-binding globulin (SHBG) transports sex steroids in blood and regulates their access to target tissues. In biological fluids, SHBG exists as a homodimer and each monomer comprises two laminin G-like domains (G domains). The crystal structure of the N-terminal G domain of SHBG in complex with 5alpha-dihydrotestosterone at 1.55 A resolution reveals both the architecture of the steroid-binding site and the quaternary structure of the dimer. We also show that G domains have jellyroll topology and are structurally related to pentraxin. In each SHBG monomer, the steroid intercalates into a hydrophobic pocket within the beta-sheet sandwich. The steroid and a 20 A distant calcium ion are not located at the dimer interface. Instead, two separate steroid-binding pockets and calcium-binding sites exist per dimer. The structure displays intriguing disorder for loop segment Pro130-Arg135. In all other jellyroll proteins, this loop is well ordered. If modelled accordingly, it covers the steroid-binding site and could thereby regulate access of ligands to the binding pocket.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Binding Sites
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Biological Transport, Active
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Calcium / metabolism
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Crystallography, X-Ray
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Dihydrotestosterone / chemistry
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Dihydrotestosterone / metabolism
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Dimerization
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Humans
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Intercellular Signaling Peptides and Proteins*
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Laminin / chemistry
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Laminin / metabolism
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Ligands
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Models, Molecular
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Molecular Sequence Data
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Protein Conformation
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Protein S / chemistry
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Protein S / genetics
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Protein S / metabolism
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Protein Structure, Quaternary
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Protein Structure, Tertiary
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Proteins / chemistry
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Proteins / genetics
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Proteins / metabolism
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Rats
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Recombinant Proteins / chemistry
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Sequence Homology, Amino Acid
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Sex Hormone-Binding Globulin / chemistry*
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Sex Hormone-Binding Globulin / genetics
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Sex Hormone-Binding Globulin / metabolism*
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Steroids / chemistry
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Steroids / metabolism
Substances
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Intercellular Signaling Peptides and Proteins
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Laminin
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Ligands
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Protein S
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Proteins
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Recombinant Proteins
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Sex Hormone-Binding Globulin
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Steroids
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growth arrest-specific protein 6
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Dihydrotestosterone
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Calcium