Ligand-activated nuclear receptor

Recently, Geick et al. [79] discovered a complex regulatory cluster of several binding sites for the ligand-activated nuclear receptor, pregnane X receptor... 

Chambon P (1996) A decade of molecular biology of retinoic acid receptors. FASEB 7 10 940-954 Wen DX, McDonnell DP (1995) Advances in our understanding of ligand-activated nuclear receptors. Curr Opin Biotechnol 6 582-589... 

Fig. 4.4. The principle of signal transduction by nuclear receptors. Nuclear receptors are ligand-controlled transcription factors that bind cognate DNA sequences, or hormone responsive elements (HRE). The hormone acts as a regulating ligand. Most nuclear receptors bind their cognate HREs, which tend to be symmetrically organized, as homo- or heterodimers. The DNA-bound, activated receptor stimulates transcription initiation via direct or indirect protein-protein interactions with the transcription initiation complex. The arrows demonstrate the different possible configurations of the HRE (see also 4.6). H hormone Hsp heat shock protein.

Apart from direct activation via ligand binding, nuclear receptors are also subject to regulation by phosphorylation. Thus, transcriptional activity of PPARy can be regulated by growth factor stimulation via the mitogen-activated protein (MAP) kinase pathway (34). 

Table 2 Nuclear receptors (NR) for enzyme inducers. Enzyme inducers are now known to act as ligands to nuclear receptors, leading to gene activation and increased synthesis of the enzyme. Affinity of inducers to die receptors is now known to be responsible for the differential induction potential and can explain die observed species-differences in induction. The receptors tabulated are aryl hydrocarbon receptors (AhR), constituitively androstane receptor (CAR), pregnane X receptor (PXR), and glucocorticoid receptor (GR). The isoforms in bold type are the major isoform regulated by the corresponding receptors.

The Glaxo group tvas the first to report the structure of a heterodimeric complex between two activated NHRs (peroxisome proliferator-activated receptor-y) PPAR-y and (retinoid X receptor-a) RXR-a. The structure (PDB entry 1FM6) of this heterodimer complex contains six components the two receptor LBDs, their two respective ligands, and two peptides derived from the steroid receptor co-activator-1 (SRC-1). These peptides contain a conserved LxxLL motif that is present in this class of co-activators. The complex is butterfly shaped, with both LBDs adopting the conserved helical sandwich fold previously reported for other ligand-bound nuclear receptors. PPAR-y contains 13 a-helices and four short / -strands, while RXR-a is composed of 11 a-helices and two short yS-strands [3]. This complex is illustrated in Fig. 1.1. 

The molecular basis for differences between mouse and human PPARa may be differences in the ability of the receptors to interact with transcriptional coactivators or to regulate miRNA cascades. Go-activators convey the transcriptional activation of the ligand-induced nuclear receptor to the transcriptional machinery. Elegant biochemical and crystallographic analyses have shown key interactions between co-activators and the ligand binding domains of nuclear receptors including PPAR family members (Li et al. 2008 Xu and Li 2008). The mouse and rat PPARa... 

---