Steroid hormones receptor structure

Mammalian nuclear receptors for steroid hormones (SHRs) are of great importance in physiology and medicine, because they control not only developmental pathways but also regulate central physiological and metabolic functions in the adult organism. Steroid hormones and vitamin D are derivatives of cholesterol. Structures of vitamin D3 and of... 

Receptors for steroid hormones located in the nucleus. These are hgand-activated transcription factors. See Lavery, D.N. and McEwan, I.J., Structure and functions of steroid receptor AFl transactivation domains induction of active conformations, Biochem. J. 391, 449 64, 2005. 

Steroid hormones perform many functions in cells, one of which is to activate gene expression by binding to steroid receptors, proteins in the cytoplasm that, when activated, act as factors that initiate transcription. All steroid hormones are derived from cholesterol and, as a result, have similar chemical structures. Steroid hormones differ one from another primarily in hydrox-ylation of particular carbon atoms and by aromatiza-tion of the steroid A ring of the molecule. Once a steroid hormone binds to a steroid receptor protein, the complex undergoes a series of structural changes that result in the complex binding to DNA at a particular sequence called a steroid response element (SRE)... 

A second type of zinc-finger structure, designated the C4 zinc finger (because it has four conserved cysteines in contact with the Zn ), is found in 50 human transcription factors. The first members of this class were identified as specific intracellular high-affinity binding proteins, or receptors, for steroid hormones, leading to the name steroid receptor superfamily. Because similar intracellular receptors for nonsteroid hormones subsequently were found, these transcrip-... 

The great variety of structures that have by now been shown to exhibit estrogenic activity leads to the suspicion that the estrogen receptor may be unusually nonspecific compared to receptors for other steroid hormones. 

This concludes what I have to say about the steroids. A constantly recurrent theme is the sensitive nature of biological activity to chemical structure. Details of chemical structure determine if and how small molecules such as steroids interact with the large molecules, say the steroid hormone receptors, to effect biological change. Such interactions are notably sensitive to molecular size and shape. 

It would be ideal if the receptor-binding capability could be directly incorporated into the peripheral structure of the ligand. Preliminary steps have been taken with the synthesis of complexes in which the exterior surfaces of the complex resemble a steroidal hormone (see Section 5.2.3.1.2), but much remains to be done to optimize receptor binding. 

The first crystal structure of the LED of the AR in complex with metri-bolone (R1881) was solved by Matias and colleagues in 2000 [38]. The LED has a similar three-dimensional structure to the other agonist-bound steroid receptors, namely the ERa, ERj6 and the PR [38]. The fact that all steroid hormone receptors bind similar hormone response elements (HREs) stands in sharp contrast to the specific activities elicited by application of the steroid... 

The hippocampus has innumerable afferent and efferent connections to other brain structures both within the limbic system and beyond. There are receptors for many different chemical signals ranging from the "classical neurotransmitters such as acetylcholine to steroid hormones and neurotrophic factors. Some of these receptors are located in the synapses that form the intrinsic hippocampal circuits and others are the targets of specific projection pathways from other brain areas. A comprehensive review of all neurotransmitter interactions relevant to function is not within the scope of this chapter. There are detailed reviews of modulation of neurochemical systems on place learning in the watermaze (McNamara and Skelton, 1993) or other limbic-system dependent tasks (Izquierdo and Medina, 1995) in animals. The effects of key neurochemical, other than NMDA channel-mediated, and environmental influences are discussed below. 

Although steroids have been studied for many years, steroid hormones continue to be a rich area of medicinal chemistry study. Steroids continue to be evaluated for their therapeutic role in the treatment of cancer, especially malignancies whose growth characteristics are hormonally responsive. In recent years, the increased recognition of the role of steroids in the brain has resulted in ongoing projects to evaluate steroids as general anasthetics and anticonvulsants. Also, the search for compounds that bind to steroid receptors, but which are not steroidal in their molecular structure, is another important area of research. 

The DNA-binding of the steroid hormone receptor occurs via an approx. 60 amino acid DNA-binding domain with two zmc-Cys4-motrfs (see also 4.3.2). The structure displays two so-called helix-loop-hehx elements, each with a boimd Zn ion (Fig. 1.6). 

Extensive deletion and mutation studies, as well as sequence comparisons, have shown that the nuclear receptors are constructed modularly. At the level of the primary structure the steroid hormone receptors can be divided into five different domains (fig. 4.5), each with specific functions. 

The steroid hormone receptors are sequence specific DNA binding proteins whose cognate DNA elements are termed hormone responsive elements" (HREs). The HREs known to date possess a common structure. They are composed primarily of two copies of a hexamer sequence. In table 4.1 are listed the hexamer sequences of the HREs of important nuclear receptors. 

The HREs of the steroid hormone receptors posses a palindromic structure, comparable to the DNA binding elements of procaryotic repressors (see fig. 4.7a). The glucocorticoid receptor, for example, binds as a homodimer to the two-fold symmetrical recognition sequence, whereby the receptor is already dimerized in solution. In complex with the DNA each subimit of the dimer contacts one half-site of the HRE. As a consequence of the two-fold repeat of the recognition sequence, a high affinity binding of the receptor dimer results (compare 1.2.4). 

Fig. 4.8. Functional domains, DNA-binding and HRE structure of the steroid hormone receptors. a) domain structure of the steroid hormone receptor. AFl, AF2 domains that mediate the stimulation of the transcription, b) schematic representation of the two Zn -Cys4 binding motils of the DNA-binding domains, c) Complex formation between the dimeric DNA-binding domains of the gluccocorticoid receptor and the HRE. The black spheres represent Zn ions. After Luisi et al., 199L d) Consensus sequence and configuration of the HRE elements of the steroid hormone receptor.

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