The Retinoic Acid Receptors RAR and RXR

In one study, it was proposed that the R274L mutation removed a polar interaction between the protein and the natural ligand VDX and created a hydrophobic hole in its place. SS-III, a derivative of VDX, was designed to fill that hole. It was prepared and found to be 286 times more potent than VDX against the mutant protein [22] (Fig. 1.18). 

Retinoid acids (RAs), the active retinoid derivatives of vitamin A, regulate complex gene networks. The pleiotropic effects of active retinoids are transduced by their cognate nuclear receptors, retinoid X receptors (RXRs) and retinoic add receptors 

Structural biology of retinoid receptor-ligand complexes focusing on the role of the ligand. 

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Retinoic Acid Receptor. Most of the biological effects of retinoids are mediated through the retinoic acid receptor (RAR) and the retinoid X receptor (RXR). Both all-/ran.s-retinoic acid and 9-d.v-rctinoic acid serve as agonists of RAR, while only 9-d.v-rctinoic acid functions as an agonist of RXR. The functional RAR exists as a heterodimer with RXR, while functional RXR exists as a homodimer. Methoprene is a juvenile hormone III analogue that mimics the activity of this insect hormone. 

The retinoid signal is transduced primarily by two distinct ligand-activated transcription factors the retinoic acid receptors (RARs) and retinoid receptors (RXRs) (Chambon, 1996). There are three distinct genes in each of the RAR and RXR gene families (a, j3, and y), all of which are activated by RA. However, not all the members of each gene family are expressed in the hindbrain. RARa is expressed up to the r3/4 border while RAR/3 is expressed uniformly in the neural tube with an anterior limit at the r6/7 boundary (Fig. 5) (Ruberte et al., 1990 Mendelsohn et al., 1991 Ruberte et al., 1991a,b, 1992, 1993 Dolle et al., 1994 Mendelsohn et al., 1994). 

R4643 9-ct s-Retinoic acid Ligands for both the retinoic acid receptor (RAR) and the retinoid X receptor (RXR) that act as transcription factors to regulate the growth and differentiation of normal and malignant cells. 

A most important function of vitamin A is in the control of cell differentiation and mrnover. PsA-trans-retinoic acid and 9-cw-retinoic acid (Figure 45-1) regulate growth, development, and tissue differentiation they have different actions in different tissues. Like the steroid hormones and vitamin D, retinoic acid binds to nuclear receptors that bind to response elements of DNA and regulate the transcription of specific genes. There are two families of nuclear retinoid receptors the retinoic acid receptors (RARs) bind all-rrijw-retinoic acid or 9-c -retinoic acid, and the retinoid X receptors (RXRs) bind 9-cw-retinoic acid. 

Figure 29-6. Gene transcription is regulated by retinoic acid.Ah-Zrwm-retinoic acid and 9-cA-retinoic acid are ligands for retinoic acid receptors (RARs) and retinoid X receptors (RXRs), respectively. The RXRs can form heterodimers with RARs and with the thyroid hormone receptors (TRs), the vitamin D receptor (VDR), and the peroxisome proliferator-activated receptors (PPARs) and a number of other hormone- and nutrient-responsive transcription factors to moderate gene transcription. Because of the ability of RXR to form heterodimers with other nuclear receptors, vitamin A has abroad effect on many hormonally and nutrient-responsive genes.

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