Homology model of human corticosteroid binding globulin: A study of its steroid binding ability and a plausible mechanism of steroid hormone release at the site of inflammation

Raja Dey, Priyobroto Roychowdhury

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Corticosteroid binding globulin (CBG) and thyroxin binding globulin (TBG) both belong to the same SERPIN superfamily of serine-proteinase inhibitors but in the course of evolution CBG has adapted to its new role as a transport agent of insoluble hormones. CBG binds corticosteroids in plasma, delivering them to sites of inflammation to modify the inflammatory response. CBG is an effective drug carrier for genetic manipulation, and hence there is immense biological interest in the location of the hormone binding site. The crystal structure of human CBG (hCBG) has not been determined, but sequence alignment with other SERPINs suggests that it conforms as a whole to the tertiary structure shared by the superfamily. Human CBG shares 52.15% and 55.50% sequence similarity with α1-antitrypsin and α1-antichymotrypsin, respectively. Multiple sequence alignment among the three sequences shows 73 conserved regions. The molecular structures of α1-antitrypsin and α1-antichymotrypsin, the archetype of the SERPIN superfamily, obtained by X-ray diffraction methods are used to develop a homology model of hCBG. Energy minimization was applied to the model to refine the structure further. The homology model of hCBG contains 371 residues (His13 to Val383). The secondary structure comprises 11 helices, 15 turns and 11 sheets. The putative corticosteroid binding region is found to exist in a pocket between β-sheets S4, S10, S11 and α helix H10. Both cortisol and aldosterone are docked to the elongated hydrophobic ligand binding pocket with the polar residues at the two extremities. A difference accessible surface area (DASA) study revealed that cortisol binds with the native hCBG more tightly than aldosterone. Cleavage at the Val379-Met380 peptide bond causes a deformation of hCBG (also revealed through a DASA study). This deformation could probably trigger the release of the bound hormone.

Original languageEnglish (US)
Pages (from-to)183-189
Number of pages7
JournalJournal of Molecular Modeling
Volume9
Issue number3
DOIs
StatePublished - Oct 20 2003
Externally publishedYes

Keywords

  • Homology model
  • Hormone release
  • Proteolytic cleavage
  • Transcortin

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