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

EMBO J. 2000 Feb 15;19(4):504-12. doi: 10.1093/emboj/19.4.504.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Biological Transport, Active
  • Calcium / metabolism
  • Crystallography, X-Ray
  • Dihydrotestosterone / chemistry
  • Dihydrotestosterone / metabolism
  • Dimerization
  • Humans
  • Intercellular Signaling Peptides and Proteins*
  • Laminin / chemistry
  • Laminin / metabolism
  • Ligands
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Conformation
  • Protein S / chemistry
  • Protein S / genetics
  • Protein S / metabolism
  • Protein Structure, Quaternary
  • Protein Structure, Tertiary
  • Proteins / chemistry
  • Proteins / genetics
  • Proteins / metabolism
  • Rats
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Sequence Homology, Amino Acid
  • Sex Hormone-Binding Globulin / chemistry*
  • Sex Hormone-Binding Globulin / genetics
  • Sex Hormone-Binding Globulin / metabolism*
  • Steroids / chemistry
  • Steroids / metabolism

Substances

  • Intercellular Signaling Peptides and Proteins
  • Laminin
  • Ligands
  • Protein S
  • Proteins
  • Recombinant Proteins
  • Sex Hormone-Binding Globulin
  • Steroids
  • growth arrest-specific protein 6
  • Dihydrotestosterone
  • Calcium

Associated data

  • PDB/1D2S