Ligands of Nuclear Receptors

Generally, the ligands of the nuclear receptors are small, rigid hydrophobic compounds with polar parts at one end, allowing binding to the receptor via Van der Waals and hydrophobic interactions and hydrogen bonds (see Section4.3.4). 

Biochemistry of Signal Transduction and Regulation. 3rd Edition. Gerhard Krauss Copyright 2003 WILEY-VCH Verlag GmbH Co. KGaA, Weinheim ISBN 3-527-30591-2 

Receptor Hormone Half site sequence configuration of HRE 

Receptor for all-trans retinoic acid, RAR all-trans retinoic acid AGTTCA IR-O, DR-2,5 ER-8 

Abbreviations IR inverted repeat DR direct repeat ER everted repeat NR no repeat . Numbers of HREs give the number of pairs separating the half-sites. R purine. Y pyrimidine. NGFI Nerve growth factor induced receptor COUP-TF CHicken ovalbumin upstream promoter transcription factor ROR Retinoic acid related orphan receptor, a, p und y are receptor subtypes coded by distinct genes. After Mangelsdorf et al, 1995. 

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CLA has also been shown to be a good ligand of nuclear receptors called peroxisome proliferator activated receptors (PPAR) (45). CLA is specifically active on two PPAR isoforms, a and y. The isoform a is found mainly in liver and functions as a transcription factor for many enzymes involved in fatty acid oxidation and particularly, peroxisomal 3-oxidation. We recently detected peroxisomal 3-oxidation products of CLA and metabolites in rat tissues and in humans (unpublished data). This finding would prompt the question whether CLA, as a good substrate for peroxisomal 3-oxidation, has any effect on peroxisomal P-oxidation. Indeed, it has been reported that induction of several key enzymes of peroxisomal P-oxidation was through the activation of PPARa by CLA (45). 

Thus, and because therapeutic effects should be maximized and side effects minimized, the characterization of nuclear receptors and their associated proteins and the ligands which interact with them will remain a challenge to pharmacologists. 

The strict control of the activity of nuclear receptors by their respective ligands has recently permitted to follow the dynamics of DNA occupancy and to discover a surprising feature, which may be true also for other enhancer-binding factors. During transcriptional activation these transcription factors do not stably reside... 

A comparison of several different steroid receptors with thyroid hormone receptors revealed a remarkable conservation of the amino acid sequence in certain regions, particularly in the DNA-binding domains. This led to the realization that receptors of the steroid or thyroid type are members of a large superfamily of nuclear receptors. Many related members of this family have no known ligand at present and thus are called orphan receptors. The nuclear receptor superfamily plays a critical role in the regulation of gene transcription by hormones, as described in Chapter 43. 

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

VOM Baur, E., et al.. Differential ligand-dependent interactions between the AF-2 activating domain of nuclear receptors and the putative transcriptional intermediary factors mSUGl andTIFl. EmboJ, 1996, 15(1),... 

This chapter deals with fluorine-containing molecules that are currently clinically used as pharmaceuticals or are at an advanced stage of their development (i.e., registered by the administration or under clinical trials I, II, or III). These compounds are found in almost all therapeutic classes and stem from very diverse chemical families. In most cases, they are inhibitors of enzymes (anti-infectious, antitumor, antiviral drugs) or are ligands of various receptors (membraneous receptors coupled to protein G, ionic channels, or nuclear receptors). 

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.

The diversity of nuclear receptor systems is also demonstrated by the fact that orphan receptors exist, which exercise a constitutive repressive or activating function independent of ligand. 

Escriva, H., Safi, R., Hanni, C., Langlois, M.C., Saumitou-Laprade, P., Stehelin, D., Capron, A., Pierce, R. and Laudet, V. (1997) Ligand binding was acquired during evolution of nuclear receptors. Proceedings of the National Academy of Sciences USA 94, 6803-6808. 

Exposure to a ligand (such as TCDD) enhances (i.e., induces) expression of the AhR gene and activates a diverse battery of other genes including CYP1A1. Variability in Ah activity has been studied extensively in animal models, and it is clear that AhR induction by arylhydrocarbons is central to understanding the pharmacogenetics of nuclear receptors (106-108). This topic is more appropriately dealt with in detail elsewhere (see Chapter 2d, Variability of induction processes, A. Okey). 

While bound to its cognate response element, the liganded/dimerized receptor recruits co-activator proteins that link with additional transcription factors, often leading to acetylation of histones, which opens up the nucleo-some to admit RNA polymerase II to the transcription start site. As would be expected, given that there is a sizeable superfamily of nuclear receptors and numerous interacting proteins, this simplified central theme is subject to many variations and complexities that allow subtle fine-tuning of regulatory responses. 

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