Nuclear receptor Structure

Bain DL, et al. Nuclear receptor structure implications for function. Annu. Rev. Physiol. 2006. 

Tenbaum S,Baniahmad A. 1997. Nuclear receptors structure, function and involvement in disease. Int. J. Biochem. Cell Biol. 29 1325 11... 

Rastinejad, E, et al. Structural determinants of nuclear receptor assembly on DNA direct repeats. Nature 375 203-211, 1995. 

Peroxisome Proliferator-Activated Receptors. Figure 1 Common structural and functional features of nuclear receptor transcription factors. Consistent with other members of the nuclear receptor superfamily, the PPARs have a modular domain structure consisting of domains A/B, C, D, and E. Each domain is associated with specific functions. 

These nuclear receptors have several common structural features (Figure 43-12). All have a centrally located DNA-binding domain (DBD) that allows the receptor to bind with high affinity to a response element. The DBD contains two zinc finger binding motifs (see Figure 39-14) that direct binding either as homodimers, as heterodimers (usually with a retinoid X... 

The second major difficulty is that cells and tissues in the body are exposed to numerous metabolites displaying different structures compared to the parent molecules present in plant foods. For example, it has been suggested that the metabolites of lycopene may be responsible for reducing the risk of developing prostate cancer. These metabolites may interact with nuclear receptors such as PPARs, LXR, and others. " Future research is needed to produce metabolites (enzymatically or chemically) in order to elucidate their cellular mechanisms and thus clarify their effects on human health. 

Waxman DJ. P450 gene induction by structurally diverse xenochemicals central role of nuclear receptors CAR, PXR, and PPAR1. Arch Biochem Biophys 1999 369 11-23. 

The zinc fingers are common structures among the transcription factors. Nevertheless, the coordination with zinc is more frequently produced between two histidine residues and two neighboring cysteines than when it is among four cysteine residues, as occurs in the nuclear hormone receptors. The zinc fingers provide an optimum architecture for the mutual recognition between specific sequences of amino acids and nucleotides. In the case of the nuclear receptors, the interaction occurs between particular amino acids of the DBD and guanine residues of the DNA sequence (Fig. 1.7). 

The chemical structure of the substances capable of interacting with a determinate nuclear receptor is tremendously varied. For now no pattern exists that permits one to assure that a particular substance is going to interact with the receptor to produce an agonist or antagonist effect. In recent years the concept of endocrine disruptors has been introduced to describe the substances that are capable of modifying the endocrine equilibrium. Some of them act by binding with nuclear hormone receptors, while others interfere with the processes of regulation of hormone secretion (Lathers 2002 Melnick et al. 2002 Nakata 2002 Powles 2002 Brown et al. 2002 Sonnenschein et al. 1998). 

There are a variety of structural classes of compounds that are active against each phosphodiesterase, and evidence suggests that selective inhibitors of PDEs can be identified. The structural diversity of PDE inhibitors provides a multitude of opportunities for development of compounds with drug-like properties. Furthermore, phosphodiesterase inhibition, which avoids direct interaction of a compound with a cell surface or nuclear receptor, may circumvent some of the target selectivity issues that can complicate receptor-based therapeutic approaches. As noted above, the specific subcellular distribution of phosphodiesterase enzymes is a key feature of their ability to modulate intracellular signaling pathways. This localization of the enzyme may minimize non-specific target... 

Benoit, G., Malewicz, M. and Perlmann, T. (2004) Digging deep into the pockets of orphan nuclear receptors insights from structural studies. Trends in Cell Biology, 14, 369-376. 

Gronemeyer, H. (2000) Nuclear receptor ligand-binding domains three-dimensional structures, molecular interactions and pharmacological implications. Trends in Pharmacological Sciences, 21, 381-388. 

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