Nuclear hormone receptors ligand-binding domains

Nuclear Hormone Receptors Ligand Binding Domains... 

Tab. 1.1 PDB codes of all nuclear hormone receptor-ligand-binding domains in the protein data bank as of December 2002.

Simons SS Jr. Structure and function of the steroid and nuclear receptor ligand-binding domain. In The Molecular Biology of Steroid and Nuclear Hormone Receptors. Freedman LP, ed. 1998. Birkhauser, Boston, pp. 35-104. 

The nuclear receptor superfamily consists of a diverse set of transcription factors that were discovered because of a sequence similarity in their DNA-binding domains. This family, now with more than 50 members, includes the nuclear hormone receptors discussed above, a number of other receptors whose ligands were discovered after the receptors were identified, and many putative or orphan receptors for which a ligand has yet to be discovered. 

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 ... 

Figure 2 Nuclear hormone receptor structure and ligands, (a) The functional domains of nuclear hormone receptors. They act as either homodimers or heterodimers with a ligand binding domain and a DNA binding domain that are separated by a linker sequence, (b) The conformational change in helix 12 when ligand binding occurs (61, 62). All-trans retinoic acid is shown behind helix 12. (c) Examples of synthetic ligands for estrogen receptor (SERMs) and thyroid hormone receptor (Thyromimetics).

Bourguet W, et al. Crystal structure of the ligand-binding domain of the human nuclear receptor RXR-a. Nature 1995 375 377-382. Feng W, et al. Hormone-dependent coactivator binding to a hydrophobic cleft on nuclear receptors. Science 1998 280 1747-1749. 

Figure 31.23. Ligand Binding to Nuclear Hormone Receptor. The ligand lies completely surrounded within a pocket in the ligand-binding domain. The last a helix, helix 12 (shovm in purple), folds into a groove on the side of the structure on ligand binding.

Figure 31.26. Coactivator Recruitmeut. The binding of ligand to a nuclear hormone receptor induces a conformational change in the ligand-binding domain. This change in conformation generates favorable sites for the binding of a coactivator.

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.]...

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