Structural analysis of the GR ligand-binding domain.

Abstract

The human glucocorticoid receptor (hGRα and hGRβ) belongs to the superfamily of nuclear receptors (NRs) which act as ligand-inducible transactivation factors (Gronemeyer and Laudet 1995; Moras and Gronemeyer 1998; Resche-Rigon and Gronemeyer 1998; McKay and Cidlowski 1999; Oakley et al. 1999). Other members of this family are the steroid (e.g. progesterone, PR; androgen, AR; mineralocorticoid, MR; oestrogen, hERα and hERβ), the thyroid (TR) and retinoic (X, RXR; acid, RAR) receptors and a variety of orphan receptors, where no ligand is known yet. Based on conserved sequence and function, all NRs can be divided into five to six domains (Bourguet et al. 2000; Egea et al. 2000). The structurally best-characterised domains are the DNA-binding domains and the ligand-binding domains (LBDs). LBDs harbour the ligand-binding pocket (LBP) as well as a ligand-dependent transactivation function. The DNA-binding domain and the LBD are both involved in receptor dimerisation. Many pharmaceutical companies aim at developing tailored ligands for the steroid LBD, to control or specifically modulate hormone-dependent processes like fertility control, osteoporosis, cancer and skin inflammatory diseases. Open image in new window Fig. 1 Overall fold of PR LBD in complex with progesterone (Williams and Sigler 1998), α-helices are shown as cylinders, β-strands as arrows. The LBP is located in the lower part of the LBD. The cartoon was prepared with the Insight2000 software (Accelrys, San Diego, USA)