A functionally orthogonal ligand-receptor pair created by targeting the allosteric mechanism of the thyroid hormone receptor
A functionally orthogonal ligand-receptor pair created by targeting the allosteric mechanism of the thyroid hormone receptor
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DOI：
10.1021/ja060760v
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发表时间：
2006-07-12
影响因子：
15
通讯作者：
Koh, John T.
中科院分区：
文献类型：
--
作者：
Hassan, A. Quamrul;Koh, John T.
核受体是一种配体依赖的转录因子，是人工调控基因表达的潜在工具。配体结合诱导涉及螺旋-12的构象变化，螺旋-12形成用于结合转录辅活化子的二聚化界面的一部分。当三碘甲腺原氨酸(T3)与甲状腺激素受体(TR)结合时，它通过中间残基His(435)和Phe(451)间接接触Helix-12，称为His-Phe开关。突变体trβ(H435A)对生理浓度的T3不敏感，但可以被合成激素类似物Qh2激活，合成激素类似物Qh2在不激活野生型受体trα和trβ的浓度下有效激活His435->；Ala突变体。QH2与野生型TRs没有表现出拮抗行为。QH2‘S与trβ(H435A)的功能正交行为在三个共同的甲状腺激素反应元件上保持不变。
Nuclear receptors are ligand-dependent transcription factors that are of interest as potential tools to artificially regulate gene expression. Ligand binding induces a conformational change involving helix-12 which forms part of the dimerization interface used to bind transcriptional coactivators. When triiodothyronine (T3) binds the thyroid hormone receptor (TR) it indirectly contacts helix-12 through intermediary residues His(435) and Phe(451) termed a His-Phe switch. The mutant TR beta(H435A) is nonresponsive to physiological concentrations of T3 but can be activated by the synthetic hormone analogue QH2 which potently activates His435 -> Ala mutant at concentrations that do not activate the wild-type receptors TR alpha and TR beta. QH2 does not show antagonist behavior with the wild-type TRs. QH2's functionally orthogonal behavior with TR beta(H435A) is preserved on the three consensus thyroid hormone response elements.