Protein Engineering, Vol. 14, No. 8, 565-571,
August 2001
© 2001 Oxford University Press
Homology modelling of the ligand-binding domain of glucocorticoid receptor: binding site interactions with cortisol and corticosterone
1 Department of Physics and 3 Department of Chemistry, University of Calcutta, 92 A.P.C. Road, Calcutta-700009, India
Glucocorticoids are involved in the growth, development and homeostasis of a number of tissues. The physiological effects of this class of lipophilic steroids are mediated by ligand-inducible nuclear transcription factor, the glucocorticoid receptor/mineralocorticoid receptor, a member of the steroid/nuclear receptor superfamily. The glucocorticoid receptor interacts specifically with glucocorticoids, whereas the mineralocorticoid receptor interacts with both glucocorticoids and mineralocorticoids. The molecular structure of progesterone complexed to its receptor obtained from X-ray crystal structure analysis is used to build up a homology model of mouse glucocorticoid receptor ligand-binding domain (mGR LBD). The secondary structure of mGR LBD contains 11 helices, nine turns and four sheets. The mGR LBD contains a long helix, H9, with 30 residues, and exhibits slight deformation when the receptor protein binds with its cognate ligands. The mGR LBD has a 12-residue C-terminal extension (residues 772–783) that is essential for hormone binding. This extension is tightly fixed in position by an antiparallel ß-sheet interaction between amino acids 680–682 (S3) and 775–777 (S4). The three-dimensional model reveals two polar sites located at the extremities of the elongated hydrophobic ligand-binding pocket. Cortisol and corticosterone are docked to this ligand-binding pocket. The difference accessible surface area study revealed the steroid-binding region of mGR LBD.
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