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  • Title: On the role of the carboxyl-terminal helix of RXR in the interactions of the receptor with ligand.
    Author: Budhu AS, Noy N.
    Journal: Biochemistry; 2000 Apr 11; 39(14):4090-5. PubMed ID: 10747799.
    Abstract:
    The retinoid X receptor (RXR), a ligand-inducible transcription factor that is activated by 9-cis-retinoic acid, is a member of the superfamily of nuclear hormone receptors. The ligand-induced transcriptional activity of nuclear receptors is coordinated by their C-terminal region termed the ligand-binding domain. Structural analyses of several nuclear receptors showed that the most dramatic ligand-induced conformational change in these proteins involves a positional shift in the receptors' C-terminal helix, termed helix 12. Consequently, in the liganded state, helix 12 is folded over the entrance to the ligand-binding pocket where it serves as a lid, and it has been proposed that this region functions to stabilize ligand binding by at least some nuclear receptors. Here, to examine the possible role of helix 12 in contributing to the association of RXR with its ligand, the equilibrium and kinetic parameters of the interactions of 9-cis-retinoic acid with RXR and with a deletion mutant lacking helix 12 were measured. Deletion of the region did not significantly alter the ligand-binding affinity of RXR at equilibrium. However, both the rate of dissociation and the rate of association of the RXR-9-cis-retinoic acid complex were significantly slower in the absence of helix 12. Taken together, these observations suggest that helix 12 of RXR facilitates both the entry and the exit of the ligand from the binding pocket without affecting the equilibrium ligand-binding affinity. The results thus point at a previously unsuspected function for this region.
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