Mechanism of the nuclear receptor molecular switch

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Abstract

Nuclear receptors are central to the regulation of development, endocrine signalling and metabolism. The transcriptional activity of many receptors is controlled through the binding of small, fat-soluble molecules to the ligand-binding domain. In most cases, ligand binding turns the receptors into potent activators of transcription. This switch involves the exchange of co-regulator proteins that mediate transcriptional regulation. Structural and biochemical studies have together revealed the mechanism of action of this ligand-induced molecular switch, in which changes in the dynamic behaviour of the receptor play a key role. This remarkable dynamic mechanism has facilitated the evolution of a family of nuclear receptors with highly diverse ligand recognition and signalling properties.

Section snippets

Specific recognition of a small-molecule ligand

There are now numerous structures of nuclear receptor ligand-binding domains (LBDs) bound to small molecules [15]. Such molecules include the natural ligands of the receptor and synthetic agonists and antagonists, as well as adventitiously bound molecules that resemble the natural ligands. By contrast, there are rather few structures of an LBD in which there is no small molecule bound.

The first thing to note from the structures is that all of the LBDs share a common, primarily helical,

Co-regulators for recruiting large complexes

A chief goal of the nuclear receptor field has been to identify the mechanisms and proteins involved in mediating the activation or repression of the receptor itself: in other words, how does ligand binding translate into regulation of transcription? This question remains to be answered in full but, at least from the point of view of the receptors, we now have a good understanding of the next step in the signalling process.

This progress has been the result of the identification of proteins that

LBDs as molecular sensors

The structural studies discussed above have revealed much of the basis of specific ligand recognition and the nature of the various co-regulator complexes. There is a difference, however, between understanding the various structures and understanding how the molecular switch functions – in other words, the mechanism through which the ligands cause a switch in the choice of co-regulator. The problem is that the structures do not provide a clear explanation for why, in the ligand-free receptor,

Concluding remarks

The realization that the dynamic behaviour of the LBD is key to the mechanism of the molecular switch explains some hitherto puzzling observations about nuclear receptors. In particular, it explains how selective modulators can fine-tune the activity of the receptor [57]. Hence, the switch is not like a regular on–off light switch, but is more like a dimmer switch. This in turn explains why some receptors, such as RAR-related orphan receptor-β (RORβ) and constitutive androstane receptor (CAR),

Acknowledgements

Work in the authors' laboratories was supported by the Royal Society, the Human Frontier Science Program (HFSP) and a Research Training Network of the European Commission (FP5), by a Research Award from the Boehringer Ingelheim Fund (to L.N.), and by a grant from the Hungarian Scientific Research Fund (T034434 to L.N.). L.N. is an International Scholar of the Howard Hughes Medical Institute and an European Molecular Biology Organization (EMBO) Young Investigator.

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