Nuclear receptor-coactivator interaction

Darimont BD, et al. Structure and specificity of nuclear receptor-coactivator interactions. Genes Dev. 1998 12 3343-3356. 

In this chapter we discuss both the insight that has been gained concerning the biological relevance of inhibiting the nuclear receptor-coactivator interaction and the progress made in the development of inhibitors for this interaction. The biological... 

Cyclization of peptides is an established strategy to stabilize short peptides in an a-helical conformation. Concomitantly, different types of cyclic peptides have been explored as inhibitors of the nuclear receptor-coactivator interaction. Guy et al. have created a library of a-helical constrained peptidomimetics, based on the second nuclear receptor box found in the SRC2 coactivator, by the introduction of a macrolactam bridge [56-58]. The macrolactam bridge induces an a-helical... 

The nuclear receptor-cofactor interaction, more specifically the nuclear receptor-coactivator interaction, has emerged as a drugable protein-protein interaction. Even though many aspects of its drugability are still unsolved, both the results obtained on the biological evaluation of its direct inhibition and the development of the first small-molecule inhibitors show the potential of targeting this interaction. 

The first CBIs have been published recently and, considering the limited amount of optimization work performed on these compounds thus far, their moderate affinity holds great promise for significant improvement. As such, these compounds provide a very good basis for optimization, proof-of-concept and selectivity studies. Independent of the ultimate biological validity ofthese compounds, these recent studies show that small molecules can be found that inhibit the nuclear receptor-coactivator interaction. 

The current studies on inhibiting the nuclear receptor-coactivator interaction have focused mainly on the ERs, AR and TR. With compounds developed against these nuclear receptors it becomes possible to also target other nuclear receptors (e.g. the orphan nuclear receptors). Here, CBIs might provide an entry for modulation of these nuclear receptors for which up to now no classical ligand has been found. 

Fowlkes, D. and McDonnell, D.P. (1999) Dissection of the LXXLL nuclear receptor— coactivator interaction motif using combinatorial peptide libraries discovery of peptide antagonists of estrogen receptors a and p. Molecular and Cellular Biology, 19, 8226-8239. 

Among the proteins that form part of the transcription machinery are found some cell factors that are produced in limited quantities. They are called cofactors of transcription (NCoA, for nuclear-receptor coactivator NCoI, for nuclear-receptor coinhibitor), formerly known as transcription intermediary factors (TIF) (McDonnell et al. 2002 McKenna et al. 1999). They constitute one of the classes of proteins that form part of the transcription machinery. These proteins are utilized by diverse types of intensifiers, that is to say, by sequences of DNA that anchor transcription factors, of which HRE are a particular case (Gruber et al. 2002 Mester et al. 1995). They do not interact directly with the DNA, but they do with the receptors and with the other elements of the transcription apparatus (Fig. 1.9). 

Mi LZ, et al. Structural basis for bile acid binding and activation of the nuclear receptor FXR. Mol. Cell 2003 11 1093-1100. Leduc AM, et al. Helix-stabilized cyclic peptides as selective inhibitors of steroid receptor-coactivator interactions. Proc. Natl. Acad. Sci. U.S.A. 2003 100 11273-11278. 

Another example is a recently discovered second mode of action by which nuclear receptors modulate transcription. In contrast to DNA-binding-dependent mechanisms, cross talk refers here to gene regulation by protein-protein-interaction of nuclear receptors with other transcription factors, such as AP-1 or NF-kB. Consequently, the nuclear receptor acts as a corepressor or coactivator of transcription. 

Beside coactivators so-called corepressors exist that are bound to transcription factors such as nuclear receptors and inhibit the initiation of transcription. These factors include the nuclear receptor corepressor (NCoR) and the silencing mediator of retinoic acid and thyroid hormone receptor (SMRT), which interact with nuclear receptors and serve as platforms for complexes containing histone deacetylases (HDACs). These enzymes cause the reversal of histone acetylation of histones leading to a tightening of chromatin and enhancing its inaccessibility for RNA polymerase containing complexes. 

Figure 43-11. The hormone response transcription unit. The hormone response transcription unit is an assembly of DNA elements and bound proteins that interact, through protein-protein interactions, with a number of coactivator or corepressor molecules. An essential component is the hormone response element which binds the ligand (A)-bound receptor (R). Also Important are the accessory factor elements (AFEs) with bound transcription factors. More than two dozen of these accessory factors (AFs), which are often members of the nuclear receptor superfamily, have been linked to hormone effects on transcription. The AFs can interact with each other, with the liganded nuclear receptors, or with coregulators. These components communicate with the basal transcription complex through a coregulator complex that can consist of one or more members of the pi 60, corepressor, mediator-related, or CBP/p300 families (see Table 43-6).

Chromatin remodeling, transcription factor modification by various enzyme activities, and the communication between the nuclear receptors and the basal transcription apparatus are accomplished by protein-protein interactions with one or more of a class of coregulator molecules. The number of these coregulator molecules now exceeds 100, not counting species variations and splice variants. The first of these to be described was the CREB-binding protein, CBP. CBP, through an amino terminal domain, binds to phosphorylated serine 137 of CREB and mediates transactivation in response to cAMP. It thus is described as a coactivator. CBP and... 

CBP/p300 has been found to interact directly with nuclear receptors and with SRC-1, thus acting synergistically to stimulate transcription (Kamei et al., 1996 Yao et al., 1996). CBP/p300 and other coactivators... 

The coactivator SRC-1 has been shown to interact with and promote the transcriptional activity of a number of nuclear receptors, including ERa (Mclnemey et al., 1996 Onate et al., 1995). More recently, we have demonstrated that SRC-1 also stimulates ERp activity through a direct interaction with its LBD, where the AF-2 domain resides (Tremblay et... 

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