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Structural insight into the mode of action of a direct inhibitor of coregulator binding to the thyroid hormone receptor.

Estébanez-Perpiñá E, Arnold LA, Jouravel N, Togashi M, Blethrow J, Mar E, Nguyen P, Phillips KJ, Baxter JD, Webb P, Guy RK, Fletterick RJ
Mol Endocrinol 21 2919-28 (2007)
Cited: 41 times
EuropePMC logo PMID: 17823305

Abstract

The development of nuclear hormone receptor antagonists that directly inhibit the association of the receptor with its essential coactivators would allow useful manipulation of nuclear hormone receptor signaling. We previously identified 3-(dibutylamino)-1-(4-hexylphenyl)-propan-1-one (DHPPA), an aromatic beta-amino ketone that inhibits coactivator recruitment to thyroid hormone receptor beta (TRbeta), in a high-throughput screen. Initial evidence suggested that the aromatic beta-enone 1-(4-hexylphenyl)-prop-2-en-1-one (HPPE), which alkylates a specific cysteine residue on the TRbeta surface, is liberated from DHPPA. Nevertheless, aspects of the mechanism and specificity of action of DHPPA remained unclear. Here, we report an x-ray structure of TRbeta with the inhibitor HPPE at 2.3-A resolution. Unreacted HPPE is located at the interface that normally mediates binding between TRbeta and its coactivator. Several lines of evidence, including experiments with TRbeta mutants and mass spectroscopic analysis, showed that HPPE specifically alkylates cysteine residue 298 of TRbeta, which is located near the activation function-2 pocket. We propose that this covalent adduct formation proceeds through a two-step mechanism: 1) beta-elimination to form HPPE; and 2) a covalent bond slowly forms between HPPE and TRbeta. DHPPA represents a novel class of potent TRbeta antagonist, and its crystal structure suggests new ways to design antagonists that target the assembly of nuclear hormone receptor gene-regulatory complexes and block transcription.

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  15. High-throughput identification of promiscuous inhibitors from screening libraries with the use of a thiol-containing fluorescent probe. McCallum MM, Nandhikonda P, Temmer JJ, Eyermann C, Simeonov A, Jadhav A, Yasgar A, Maloney D, Arnold AL. J Biomol Screen 18 705-713 (2013)
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  19. Similarities and differences between two modes of antagonism of the thyroid hormone receptor. Sadana P, Hwang JY, Attia RR, Arnold LA, Neale G, Guy RK. ACS Chem Biol 6 1096-1106 (2011)
  20. Synthesis and evaluation of methylsulfonylnitrobenzamides (MSNBAs) as inhibitors of the thyroid hormone receptor-coactivator interaction. Hwang JY, Attia RR, Carrillo AK, Connelly MC, Guy RK. Bioorg Med Chem Lett 23 1891-1895 (2013)
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