2PIN

Thyroid receptor beta in complex with inhibitor

Summary for 2PIN

• Entry DOI: 10.2210/pdb2pin/pdb
• Related: 2PIO 2PIP 2PIQ 2PIR 2PIT 2PIU 2PIV 2PIW 2PIX 2PKL
• Descriptor: Thyroid hormone receptor beta-1, [4-(4-HYDROXY-3-IODO-PHENOXY)-3,5-DIIODO-PHENYL]-ACETIC ACID, 1-(4-HEXYLPHENYL)PROP-2-EN-1-ONE, ... (5 entities in total)
• Functional Keywords: thyroid receptor beta, nuclear receptors, inhibitors, protein-protein interactions, coregulator binding, af-2 pocket, aromatic-beta-amino ketones, structure-based drug design, surface interacting drugs, hormone receptor
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: P10828
• Total number of polymer chains: 2
• Total formula weight: 59020.94

Authors

Estebanez-Perpina, E.,Jouravel, N.,Baxter, J.D.,Guy, L.R.,Webb, P.,Fletterick, R.J. (deposition date: 2007-04-13, release date: 2008-02-26, Last modification date: 2024-02-21)

Primary citation

Estebanez-Perpina, E.,Arnold, L.A.,Jouravel, N.,Togashi, M.,Blethrow, J.,Mar, E.,Nguyen, P.,Phillips, K.J.,Baxter, J.D.,Webb, P.,Guy, R.K.,Fletterick, R.J.
Structural insight into the mode of action of a direct inhibitor of coregulator binding to the thyroid hormone receptor.
Mol.Endocrinol., 21:2919-2928, 2007

PubMed 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.

PubMed: 17823305
DOI: 10.1210/me.2007-0174

Experimental method

X-RAY DIFFRACTION (2.3 Å)