Crystal structure of human sex hormone-binding globulin: steroid transport by a laminin G-like domain.
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.
Grishkovskaya
I
I
Forschungsgruppe Kristallographie, Max-Delbrück-Center for Molecular Medicine, Robert-Roessle-Strasse 10, D-13092 Berlin, Germany.
Avvakumov
G V
GV
Sklenar
G
G
Dales
D
D
Hammond
G L
GL
Muller
Y A
YA
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D001693:Biological Transport, Active; D002118:Calcium / Q000378:metabolism; D018360:Crystallography, X-Ray; D013196:Dihydrotestosterone / Q000737:chemistry / Q000378:metabolism; D019281:Dimerization; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007797:Laminin / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017293:Protein S / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D012738:Sex Hormone-Binding Globulin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D013256:Steroids / Q000737:chemistry / Q000378:metabolism; D000099255:Growth Arrest-Specific Protein 6
D002118:Calcium; D013196:Dihydrotestosterone; D036341:Intercellular Signaling Peptides and Proteins; D007797:Laminin; D008024:Ligands; D017293:Protein S; D011506:Proteins; D011994:Recombinant Proteins; D012738:Sex Hormone-Binding Globulin; D013256:Steroids; D000099255:Growth Arrest-Specific Protein 6