Ligand binding domain

The main function of the ligand-binding domain (LBD) is to bind ligand and it is helped in this task by molecular chaperones. Genetic and biochemical studies have shown that the chaperones Hsp90 and Hsp70 participate in the activation process of the receptor. They maintain the apoAR (AR in the absence of hormone) in a high affinity ligand-binding conformation which is important for efficient response to hormone (Caplan etal. 1995; Fang etal. 1996).

To understand the specific recognition of ligands by the human AR, homology models of the ligand-binding domain were constructed based on the crystal structure of the progesterone receptor ligand binding domain. Several mutants in residues potentially involved in the specific recognition of ligands in the hAR were constructed and tested for their ability to bind agonists (Poujol et al. 2000). The homology model AR was refined using unrestrained multiple molecular dynamics simulations in explicit solvent (Marhefka etal. 2001). These models together with the recent crystal structure of the AR, show that the HBD of the AR is similar in structure to the HBD of other nuclear receptors. It is composed of 12 helices and a small (p-sheet arranged in an a-helical sandwich. Depending on the nature of the ligand, agonists or antagonists, the carboxy-terminal helix H12 is found in either one of two orientations. In the agonists-bound conformation, helix H12 serves as a lid to close the ligand-binding pocket, whereas in the antagonist-bound conformation, helix H12 is positioned in a different orientation, thus opening the entrance of the ligand-binding pocket (Matias et al. 2000). The structure of the LBD of the wild-type AR and the T877A mutant found in the LNCaP prostate cancer cells that provide the receptor with a broad steroid specificity have been refined at 2.0A resolution (Sack et al. 2001). The crystal structure of the mutant AR (L701H and T877A) reported to bind cortisol/cortisone with high affinity has however been determined at 1.95A (Matias etal. 2002). These structural studies provide mechanistic explanation why non-androgenic ligands do function as agonists when bound to the AR.

Hair Loss Prevention

Hair Loss Prevention

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