Review
Nuclear receptor ligand-binding domains: three-dimensional structures, molecular interactions and pharmacological implications

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Abstract

Nuclear receptors are members of a large family of ligand-inducible transcription factors that regulate gene programs underlying a plethora of (patho)physiological phenomena. The recent determination of the crystal structures of nuclear receptor ligand-binding domains has provided an extremely detailed insight into the intra- and intermolecular mechanisms that constitute the initial events of receptor activation and signal transduction. Here, a comprehensive mechanistic view of agonist and antagonist action will be presented. Furthermore, the novel class of partial agonists–antagonists will be described and the multiple challenges and novel perspectives for nuclear-receptor-based drug design will be discussed.

Section snippets

Allosteric effects induced by agonists

It is well known that ligand binding induces a conformational change in nuclear receptors, and protease digestion and antibody accessibility studies reveal that agonists and antagonists trigger distinct structural alterations of nuclear receptor LBDs. The resolution of the crystal structures of several ligand-free (apo) and ligand-occupied (holo) nuclear receptor LBDs alone or in a complex with co-activator fragments have provided molecular details of the various ligand-induced changes and,

Structural basis of antagonist action

To date, three crystals of nuclear receptor LBDs bound to pure AF-2 antagonists (Fig. 3) have been reported. The structural determination of the ERα LBD in complexes with the selective anti-oestrogens raloxifen16 and 4-hydroxy-tamoxifen12, provided the first structural evidence for the structural basis of antagonism. This principle was recently extended to another subgroup of the nuclear receptor family with the determination of the structure of the retinoic acid receptor α (RARα) LBD bound to

Structural basis for full and partial AF-2 antagonism

In addition to complete antagonists of AF-2 function (e.g.raloxifen and 4-hydroxytamoxifen), AF-2 partial agonists–antagonists (Fig. 3) have been crystallized with the corresponding receptors. All the structures discussed above show a strict correlation between the orientation of the AF-2 helix and their biological activity. However, the ERβ–genistein19 and RXRα–F318A–oleic acid17 LBD structures show that H12 can adopt the antagonist conformation even though the corresponding ligand elicits a

Orphan receptors as new pharmacological targets

Because of its implication in virtually all fundamental physiological functions, the nuclear receptor superfamily offers an exceptional spectrum of targets for the development of therapeutics. In addition, the rapidly growing number of nuclear receptor superfamily members raises the prospects of new targets and new ligands. Indeed, recently, ligands for several of these new nuclear receptors, the so-called orphan receptors1, 22, have been identified. One example are PPARs whose α isotype was

Acknowledgements

We thank Dino Moras and all colleagues of the structural biology group at the IGBMC for sharing unpublished information and instructive discussions. Studies in our laboratory are supported by funds from the INSERM, CNRS, Hôpital Universitaire de Strasbourg (HUS), the Fondation pour la Recherche Médicale, the Ministère de la Recherche et de la Technologie and Bristol-Myers-Squibb.

Glossary

Chemical names

BMS394 and BMS395:
R- and S-3-fluoro-4-[2-hydroxy-2-(5,5,8,8-tetramethyl-5,6,7,8,-tetrahydro-naphthalen-2-yl)-acetylamino]-benzoic acid
BMS614:
4-[(4,4-dimethyl-1,2,3,4-tetrahydro-[1, 2′]binaphthalenyl-7-carbonyl)-amino]-benzoic acid
BMS961:
racemic mixture of BMS394 and BMS395
G1262570:
(2S)-((2-benzoylphenyl)amino)-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenyl} propionic acid
GW0072:
(+/−)-(2S, 5S)-4-(4-(4-carboxyphenyl) butyl)-2-heptyl-4-oxo-5-thiazolidine N,N-dibenzylacetamide
GW2433:

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