Vitamin A, in the form of retinol and retinoic acid, is vital to a number of biological functions. A specific transport system exists to deliver the vitamin to the target cells, where intracellular carrier proteins mediate the function of this hydrophobic molecule. Independent laboratories have put forth the hypothesis that the retinoids mediate cell function in a manner analogous to that of the steroid hormones i.e., that they control gene expression by interacting with nuclear receptors. Important support for this hypothesis has come from the identification by two independent laboratories of a nuclear receptor for retinoic acid which regulates gene expression. It has been suggested that since the retinoids have roles analogous to those of the steroid hormones, retinoids themselves could become as important in clinical medicine as the steroids. Such a role in clinical medicine and pharmacology suggests that structural information with respect the nature of these interactions, could contribute to the development of new pharmaceuticals. We have shown that an androgen-dependent protein from rat epididymis, which is thought to play a role in sperm maturation, binds retinoic acid. The epididymal protein is in the same super family as the serum retinol-binding protein and it is predicted that it has a similar tertiary structure, despite less than 20% sequence homology. In contrast to the serum protein, however, the epididymal retinoic-acid binding protein clearly discriminates between retinol and retinoic acid. We have previously determined the X-ray crystallographic structure of the human serum retinol-binding protein, the protein which mediates the transport of retinol from its storage site in the liver to the various target tissues. The protein structure was determined with retinol bound. A comparison of these two protein structures and their binding sites and specificities, will provide us with an excellent system in which to study retinoid recognition. We have obtained X-ray diffraction quality crystals for the epididymal retinoic acid-binding protein with and without retinoic acid.
