Arg²⁷⁸, but not Lys²²⁹ or Lys²³⁶, plays an important role in the binding of retinoic acid by retinoic acid receptor γ

The diverse biological actions of retinoic acid (RA) are mediated by retinoic acid receptors (RARα, β and γ) and retinoid X receptors (RXR α, β, and γ). Although the ligand-binding domains of RARs share the same novel folding pattern, many RAR subtype-specific retinoids have been synthesized indicating that the ligand-binding pocket of each RAR subtype has unique features. Previously we have demonstrated the importance for HA binding and RA-dependent transactivation of Arg²⁷⁶ of RARα alone and in RARβ Arg²⁶⁹ in conjunction with Lys²²⁰. In this study, we have examined the role of the homologous amino acid residues (Lys²²⁹ and Arg²⁷⁸) in RARγ for these activities. Like RARα but dissimilar to RARβ Arg²⁷⁸ in RARγ alone was found to play an important role in RA binding and RA-dependent transactivation. Since Lys²³⁶ in RARγ was suggested from the crystal structure of holo-RARγ, to interact with RA, we also examined its role and that of its homologs in RARα and RARβ. Despite the suggestion from the crystal structure, neither Lys²³⁶ nor its homologs in RARα and RARβ play a role in the binding of RA or RA-dependent transactivation. It is likely that Lys²³⁶ in RARγ and its homologs in RARα and RARβ are solvent exposed rather than pointing into the RA-binding pocket.