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Structural Insight into the Mode of Action of a Direct Inhibitor of Coregulator Binding to the Thyroid Hormone Receptor

Department of Biochemistry and Biophysics (E.E.-P., N.J., E.M., R.J.F.), University California San Francisco, San Francisco, California 94158; Department of Chemical Biology and Therapeutics (L.A.A., R.K.G.), St. Jude Children’s Research Hospital, Memphis, Tennessee 38105; and Diabetes Center and Department of Medicine (M.T., P.N., K.J.P., J.D.B., P.W.) and Department of Cellular and Molecular Pharmacology (J.B.), University California San Francisco, San Francisco, California 94143

Address all correspondence and requests for reprints to: Robert J. Fletterick, Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158-2240. E-mail: flett{at}msg.ucsf.edu.

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 β-amino ketone that inhibits coactivator recruitment to thyroid hormone receptor β (TRβ), in a high-throughput screen. Initial evidence suggested that the aromatic β-enone 1-(4-hexylphenyl)-prop-2-en-1-one (HPPE), which alkylates a specific cysteine residue on the TRβ 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 TRβ with the inhibitor HPPE at 2.3-Å resolution. Unreacted HPPE is located at the interface that normally mediates binding between TRβ and its coactivator. Several lines of evidence, including experiments with TRβ mutants and mass spectroscopic analysis, showed that HPPE specifically alkylates cysteine residue 298 of TRβ, which is located near the activation function-2 pocket. We propose that this covalent adduct formation proceeds through a two-step mechanism: 1) β-elimination to form HPPE; and 2) a covalent bond slowly forms between HPPE and TRβ. DHPPA represents a novel class of potent TRβ 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.

NURSA Molecule Pages Link:

Nuclear Receptors:   TRα  |  TRβ

Coregulators:   GRIP1  |  NCoR

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