Crystal structure of human sex hormone-binding globulin: steroid transport by a laminin G-like domain

被引:130
作者
Grishkovskaya, I
Avvakumov, GV
Sklenar, G
Dales, D
Hammond, GL
Muller, YA
机构
[1] Max Delbruck Ctr Mol Med, Forsch Grp Kristallog, D-13092 Berlin, Germany
[2] Univ Western Ontario, Dept Obstet & Gynaecol, London, ON N6A 4L6, Canada
[3] Univ Western Ontario, Dept Pharmacol & Toxicol, MRC, Grp Fetal & Neonatal Hlth & Dev, London, ON N6A 4L6, Canada
关键词
calcium binding; dimerization; jellyroll fold; plasma protein; sex steroids;
D O I
10.1093/emboj/19.4.504
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 5 alpha-dihydrotestosterone at 1.55 Angstrom 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 Angstrom 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.
引用
收藏
页码:504 / 512
页数:9
相关论文
共 76 条
[1]  
AVVAKUMOV GV, 1991, LECTINS CANCER, P263
[2]   THE CCP4 SUITE - PROGRAMS FOR PROTEIN CRYSTALLOGRAPHY [J].
BAILEY, S .
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 1994, 50 :760-763
[3]  
BANASZAK L, 1994, ADV PROTEIN CHEM, V45, P89
[4]   Secondary structure and shape of plasma sex steroid-binding protein - Comparison with domain G of laminin results in a structural model of plasma sex steroid-binding protein [J].
Beck, K ;
Gruber, TM ;
Ridgway, CC ;
Hughes, W ;
Sui, LM ;
Petra, PH .
EUROPEAN JOURNAL OF BIOCHEMISTRY, 1997, 247 (01) :339-347
[5]   STRUCTURE AND FUNCTION OF LAMININ - ANATOMY OF A MULTIDOMAIN GLYCOPROTEIN [J].
BECK, K ;
HUNTER, I ;
ENGEL, J .
FASEB JOURNAL, 1990, 4 (02) :148-160
[6]   Merging extracellular domains: Fold prediction for laminin G-like and amino-terminal thrombospondin-like modules based on homology to pentraxins [J].
Beckmann, G ;
Hanke, J ;
Bork, P ;
Reich, JG .
JOURNAL OF MOLECULAR BIOLOGY, 1998, 275 (05) :725-730
[7]  
BLAKE CCF, 1977, NATURE, V268, P115, DOI 10.1038/268115a0
[8]   STEROID-BINDING AND DIMERIZATION DOMAINS OF HUMAN SEX HORMONE-BINDING GLOBULIN PARTIALLY OVERLAP - STEROIDS AND CA2+ STABILIZE DIMER FORMATION [J].
BOCCHINFUSO, WP ;
HAMMOND, GL .
BIOCHEMISTRY, 1994, 33 (35) :10622-10629
[9]   STRUCTURE-FUNCTION ANALYSES OF HUMAN SEX HORMONE-BINDING GLOBULIN BY SITE-DIRECTED MUTAGENESIS [J].
BOCCHINFUSO, WP ;
WARMELSRODENHISER, S ;
HAMMOND, GL .
FEBS LETTERS, 1992, 301 (02) :227-230
[10]  
CHAMBON CP, 1997, THESIS U C BERNARD L