作为一种必需的初级激素,甲状腺激素(TH)是人体生长不可缺少的,发育和新陈代谢。TH功能在几个方面受损,包括TH合成,激活,运输和受体依赖性反式激活,最终会导致甲状腺激素抵抗综合征(RTH)。RTH是一种罕见的综合征,表现为靶细胞对TH信号的反应降低。大多数RTH病例与甲状腺激素受体β(TRβ)突变有关,只有少数RTH病例与甲状腺激素受体α(TRα)突变或其他原因有关。RTH患者患有甲状腺肿,智力迟钝,身材矮小和心动过缓或心动过速。迄今为止,在RTH患者中已经报道了大约170个突变的TRβ变体和超过20个突变的TRα变体。除了这些突变的蛋白质,一些TR同工型还可以通过与初级TR竞争TRE和RXR结合来降低TH功能。幸运的是,通过构效关系(SAR)研究和药物设计探索了RTH的不同治疗方法,在这些治疗中。具有模拟甲状腺的效力,但生化特性与原发性TH(T3和T4)不同,这些TH类似物可以绕过特定的缺陷转运蛋白或反应性突变TR。然而,这些化合物必须小心使用,以避免过度激活TRα,这与更严重的心脏损伤有关。本文综述了突变诱导的TR配体结合域RTH的结构机制。此外,还讨论了克服这种耐药性的治疗策略。
As an essential primary hormone, thyroid hormone (TH) is indispensable for human growth, development and metabolism. Impairment of TH function in several aspects, including TH synthesis, activation, transportation and receptor-dependent transactivation, can eventually lead to thyroid hormone resistance syndrome (RTH). RTH is a rare syndrome that manifests as a reduced target cell response to TH signaling. The majority of RTH cases are related to thyroid hormone receptor β (TRβ) mutations, and only a few RTH cases are associated with thyroid hormone receptor α (TRα) mutations or other causes. Patients with RTH suffer from goiter, mental retardation, short stature and bradycardia or tachycardia. To date, approximately 170 mutated TRβ variants and more than 20 mutated TRα variants at the amino acid level have been reported in RTH patients. In addition to these mutated proteins, some TR isoforms can also reduce TH function by competing with primary TRs for TRE and RXR binding. Fortunately, different treatments for RTH have been explored with structure-activity relationship (SAR) studies and drug design, and among these treatments. With thyromimetic potency but biochemical properties that differ from those of primary TH (T3 and T4), these TH analogs can bypass specific defective transporters or reactive mutant TRs. However, these compounds must be carefully applied to avoid over activating TRα, which is associated with more severe heart impairment. The structural mechanisms of mutation-induced RTH in the TR ligand-binding domain are summarized in this review. Furthermore, strategies to overcome this resistance for therapeutic development are also discussed.