Research in the May issue of Nature Structural Biology has shown that a small molecule known as THC antagonizes oestrogen receptor-β (ER-β) by means of a novel mechanism. THC blocks transcription without the usual physical obstruction of the positioning of helix 12 in the ER-β protein, which is necessary for receptor activation. Interestingly, whereas THC acts as an antagonist of ER-β, it is an agonist of ER-α. This study solved the crystal structures of THC bound to the ligand-binding domains of both ER-α and ER-β, in order to investigate the mechanisms of THC agonism and antagonism.
Both ER-α and ER-β mediate the physiological effects of both endogenous and synthetic oestrogens. These receptors are members of the nuclear-receptor superfamily of ligand-regulated transcription factors. The ligand-binding domains of ER-α and ER-β each have a transcriptional activation function, which is responsive to agonists, including oestrogen 17β-oestradiol (E2) and diethylstilbestrol. Antagonists, such as 4-hydroxytamoxifen and raloxifene, block the activation-function activity. Agonists stabilize a conformation of the receptor in which helix 12 lies across the opening of the binding pocket, thereby allowing the receptor to interact with the transcriptional co-activators that mediate ligand-dependent transcription of the receptor. Most ER antagonists have bulky side chains that cannot fit within the binding pocket, and so ER-β helix 12 cannot adopt the agonist-bound conformation, which occludes binding to transcriptional co-activators. But because THC lacks the bulky side chain that is typical of other ER antagonists, it must antagonize ER-β through a different mechanism.
Comparing the crystal structures of THC bound to either ER-β or ER-α shows that although THC binds to both chains in a similar manner overall, it fails to stabilize several of the binding-pocket interactions with ER-β in comparison to those with ER-α. The slight differences in sequence between the two ERs means that crucial residues in ER-β adopt a random-coil conformation instead of a helical one. This does not favour the agonist-bound conformation of helix 12, and actually stabilizes an inactive conformation of the helix.
This new type of antagonism is probably not unique to THC and ER-β. There are other examples of nuclear-receptor ligands that act as antagonists, even though they might be smaller than the endogenous agonists. Flutamide, a synthetic androgen-receptor antagonist, is similar in size to testosterone, and does not have a bulky side chain to act as an antagonist. Also, progesterone is smaller than aldosterone, but is a high-affinity antagonist of the mineralocorticoid receptor.
This insight into such non-classical antagonism of nuclear receptors highlights a new possible approach to designing antagonists, in which compounds could be tailored to selectively stabilize inactive conformations of certain nuclear receptors, and the active conformations of others.
References
ORIGINAL RESEARCH PAPER
Shiau, S. K. et al. Structural characterisation of a subtype-selective ligand reveals a novel mode of estrogen receptor antagonism. Nature Struct. Biol. 9, 359–364 (2002)
FURTHER READING
Kenakin, T. Efficacy at G-protein-coupled receptors. Nature Rev. Drug Disc. 1, 103–110 (2002)
Christopoulos, A. Allosteric binding sites on cell-surface receptors: novel targets for drug discovery. Nature Rev. Drug Disc. 1, 198–210 (2002)
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Brazil, M. Blocking without obstruction. Nat Rev Drug Discov 1, 330 (2002). https://doi.org/10.1038/nrd808
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DOI: https://doi.org/10.1038/nrd808