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 alpha1-antitrypsin and alpha1-antichymotrypsin, respectively. Multiple sequence alignment among the three sequences shows 73 conserved regions. The molecular structures of alpha1-antitrypsin and alpha1-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 beta-sheets S4, S10, S11 and alpha 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. Figure Stereoscopic view of the ribbon diagram of hCBG complexed with
cortisol. The bound
cortisol is shown in space filling model in blue. Helices and sheets are shown in red and magenta respectively. Turns are shown in yellow.