Nuclear receptors are a class of ligand activated intracelluartranscription factors which up or down regulate the expression of genes.[1]
Nuclear receptors may be classified either according to mechanism (type I or II),[2] or sequence homology (NR subfamilies 0-6)[3] (see respectively mechanism and homology classifications below).
Ligands that bind to nuclear receptors include lipophilic substances such as endogenoushormones, vitamins A and D, drugs, and xenobioticendocrine disruptors. Because the expression of a large number of genes is regulated by nuclear receptors, ligands that bind to these receptors can have profound effects on the organism.
A number of nuclear receptors, referred to as orphan receptors, have no known (or at least generally agreed upon) endogenous ligands. Some of these receptors such as FXR, LXR, and PPAR bind a number of metabolic intermediates such as fatty acids, bile acids and/or sterols with relatively low affinity. These receptors hence may function as metabolic sensors. Other nuclear receptors, such as CAR and PXR appear to function as xenobiotic sensors upregulating the expression of cytochrome P450 enzymes that metabolize these xenobiotics.[4]
A few other nuclear receptors, such as the constitutive androstane receptor appear to be active in the absence of ligand. Finally seveal nuclear receptors such as the short heterodimer partner (SHP; NR0B2), lack a ligand binding domain and therefore by definition cannot bind ligand.
Structural Oragnization of Nuclear Receptors Top – Schematic 1D amino acid sequence of a nuclear receptor. Bottom – 3D structures of the DBD (bound to DNA) and LBD (bound to hormone) regions of the nuclear receptor. The structures shown are of the estrogen receptor. Experimental structures of N-terminal domain (A/B), hinge region (D), and C-terminal domain (E) have not been determined therefore are represented by red, purple, and orange dashed lines respectively.
Nuclear receptors contain the following structural domains:[5]
Mechanism of Nuclear Receptor Action Small lipophilic substances such as natural hormones diffuse past the cell membrane and bind to nuclear receptors located in the cytosol of the cell. This causes a change in the conformation of the nuclear receptor which in turn causes the receptor to dimerize, translocate into the cell nucleus, and bind to a specific sequence of DNA called a hormone response element (HRE). The receptor/DNA complex recruits other proteins with in the cell to transcribe DNA downstream from the HRE into messenger RNA and then into protein which causes a change in cell function.
Nuclear receptors may be classified into the following two mechanistic classes:[2]
The nuclear receptor/DNA complex then recruits other proteins which transcribe DNA downstream from the HRE into messenger RNA and eventually protein which causes a change in cell function.
Type II
Type II receptors (NR subfamily 1) in contrast are retained in the nucleus regardless of the ligand binding status and in addition bind as hetero-dimers (usually with RXR) to DNA.
^ Evans, R.M. The steroid and thyroid hormone receptor superfamily. Science. 1988240(4854):889-895. PMID 3283939.
^ ab Novac N, Heinzel T. Nuclear receptors: overview and classification. Curr. Drug Targets Inflamm. Allergy. 2004; 3(4):335-46. PMID 15584884
^ abc Nuclear Receptors Nomenclature Committee. A unified nomenclature system for the nuclear receptor superfamily. Cell. 1999; 97(2):161-3. PMID 10219237
^ Mohan R, Heyman RA, Orphan nuclear receptor modulators. Curr Top Med Chem.2003; 3(14):1637-47. PMID 14683519
^ Klinge CM, Estrogen receptor interaction with co-activators and co-repressors. Steroids. 2000; 65(5):227-51. PMID 10751636
^ Zhang Z, Burch PE, Cooney AJ, Lanz RB, Pereira FA, Wu J, Gibbs RA, Weinstock G, Wheeler DA. Genomic analysis of the nuclear receptor family: new insights into structure, regulation, and evolution from the rat genome. Genome Res.2004; 14(4):580-90. PMID 15059999
^ Wu W, Niles EG, El-Sayed N, Berriman M, LoVerde PT. Schistosoma mansoni (Platyhelminthes, Trematoda) nuclear receptors: sixteen new members and a novel subfamily. Gene. 2006. 366(2):303-15. PMID 16406405
^ Wu W, Niles EG, Hirai H, LoVerde PT. Evolution of a novel subfamily of nuclear receptors with members that each contain two DNA binding domains. BMC Evol Biol. 2007, 7:27.PMID 17319953
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