The repressive and activating states of nuclear hormone receptors are achieved through the recruitment of cofactor proteins. The binding of co-repressors and co-activators is believed to be mutually exclusive and principally regulated by ligand binding. To understand the molecular determinants of the switch induced by ligand in the @entity1968 receptor and in particular the intrinsic role of the @entity6340 ( @entity6340 ) in cofactor binding and release, we carried out extensive mutational analysis of surface residues of the @entity6340 . As seen previously we found that co-repressor and co-activator molecules bind to overlapping docking sites on the surface of the @entity1968 receptor alpha @entity6340 . Perturbation of this surface impaired both co-activator and co-repressor association resulting in a transcriptionally inert receptor. Unexpectedly mutation of two residues, Trp-225 and Ala-392, which lie outside the docking site, had opposite effects on co-activator and co-repressor binding. W225A was a constitutive repressor that failed to bind co-activator and exhibited an increased, and ligand-insensitive, interaction with co-repressor. @entity70044 , on the other hand, had reduced affinity for co-repressors and increased affinity for co-activators and behaved as a constitutive, but still ligand-inducible, activator. Analysis of known structures showed that these mutations lie in the proximity of helix 12 (H12), and their effects are likely to be the result of perturbations in the behavior of H12. These data suggest that residues in the close vicinity of H12 regulate cofactor affinity and determine the basal activity of receptors.

Molecular determinants of the balance between co-repressor and co-activator recruitment to the XXXX receptor.

@entity6340 :: ('MESH:D006938', 'Disease') :: ['LBD', 'ligand binding domain'] @entity70044 :: ('p|SUB|A|392|R', 'ProteinMutation') :: ['A392R'] @entity1968 :: ('MESH:D014212', 'Chemical') :: ['retinoic acid']
@entity1968 :: (MESH:D014212,Chemical) :: ['retinoic acid']
