Minireview: dynamic structures of nuclear hormone receptors: new promises and challenges

Abstract

Therapeutic targeting of nuclear receptors (NRs) is presently restricted due to 2 constraints: 1) a limited knowledge of the structural dynamics of intact receptor when complexed to DNA and coregulatory proteins; and 2) the inability to more selectively modulate NR actions at specific organ/gene targets. A major obstacle has been the current lack of understanding about the function and structure of the intrinsically disordered N-terminal domain that contains a major regulatory transcriptional activation function (AF1). Current studies of both mechanism of action and small molecule-selective receptor modulators for clinical uses target the structured pocket of the ligand-binding domain to modulate coregulatory protein interactions with the other activation function AF2. However, these approaches overlook AF1 activity. Recent studies have shown that highly flexible intrinsically disordered regions of transcription factors, including that of the N-terminal domain AF1 of NRs, not only are critical for several aspects of NR action but also can be exploited as drug targets, thereby opening unique opportunities for endocrine-based therapies. In this review article, we discuss the role of structural flexibilities in the allosteric modulation of NR activity and future perspectives for therapeutic interventions.

Figure 1.

A model showing disorder-order transition of ID NTD of NRs. The ID NTDs exist as an ensemble of conformers in equilibrium with each other, which are collectively unstructured. Except for a very small fraction, which may be relatively ordered, all other conformers possess the characteristics of random coil or molten globule-like structures (A). When encountered by a binding partner protein (often a coregulatory protein), the ID NTD undergoes disorder-order transition by first undergoing various partial folded conformations (B) that finally results into functionally folded NTD conformation (C). In the full-length receptor this conformational transition is influenced by several other allosteric regulators (data not shown).

Figure 2.

Various inter- and intramolecular avenues exist for allosteric regulation of NR activity. Shown is a representative folded SHR structure resulting from both posttranslational modifications (“P” inside green circles) and the association (indicated by arrow) of ligand, DNA, and AF1- and AF2-binding proteins (which can be the same molecule interacting at 2 sites). Binding of different molecules in the ligand-binding pocket can pass the signal to the surface of the LBD and dynamically reorient AF2/H12 conformation and other parts of the domain. Signals and consequent conformational changes are then passed (double-ended blue arrows) either sequentially or directly to the hinge, DBD, and/or ID NTD/AF1. In a similar fashion, (hormone response element (HRE)-DBD binding passes signals to influence the structure of NTD/AF1 and/or the AF2 surface. Direct binding of coregulatory proteins, site-specific phosphorylation, and possibly other posttranslational modifications (P), and even ID NTD/AF1-flanking sequences within the NTD can be avenues for allosteric coupling involving ID NTD/AF1 and other receptor domains. The structures/shapes shown for each domain are only representative and are not actual conformations.