Ligand-bound nuclear hormone receptor

The use of structure-based virtual screening toward novel nuclear hormone receptor antagonists was described by Schapira et al. [263]. As only X-ray structures of ligand binding domains of agonist-bound nuclear receptors with exception of the antagonist-bound estrogen receptor-a are available, the authors constructed an inactive ... 

Conformational restriction is a very powerful method for probing the bioactive conformations of peptides. Small peptides have many flexible torsion angles so that enormous numbers of conformations are possible in solution. For example, a simple tripeptide such as thyrotropin-releasing hormone (TRH 7) (Fig. 15.4) with six flexible bonds could have over 65,000 possible conformations. The number of potential conformers for larger peptides is enormous, and some method is needed to exclude potential conformers. Modem biophysical methods, e.g., X-ray crystallography or isotope edited nuclear magnetic resonance (NMR), (33) can be used to characterize peptide-protein interactions for soluble proteins, but most biophysical methods cannot yet determine the conformation of a ligand bound to constitutive receptors, e.g., G-protein-coupled receptors (34, 35). 

Figure 31.26 Structure of two nuclear hormone receptor domains. Nuclear hormone receptors contain two crucial conserved domains (1) a DNA-binding domain toward the center of the sequence and (2) a ligand-binding domain toward the carboxyl terminus. The str ucture of a dimer of the DNA=binding domain bound to DNA is shown, as is one monomer of the normally dimeric ligand-binding domain. [Drawn from IHCQ and ILBD.pdb.]...

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.

CRABP (1) and CRABP (11) function to transport retinoic acid into the nucleus for binding to retinoid receptors. CRABP(ll), with retinoic acid bound, also interacts directly with the liganded RAR-RXR heterodimer bound to hormone response elements on DNA and enhances the activity of the nuclear receptor (Section2.3.2.1 Delvaetal., 1999). 

Steroid hormone receptors are homodimeric nuclear receptors. In the absence of hormone, they are trapped in the cytoplasm by inhibitor proteins. When bound to their ligands, they can translocate to the nucleus and activate transcription of target genes (see Figure 11-44). 

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