Hormone selectivity in thyroid hormone receptors.
Hormone selectivity in thyroid hormone receptors.
复制标题
DOI：
10.1210/mend.15.3.0608
复制
发表时间：
2001-03
影响因子：
--
通讯作者：
R. Wagner;B. R. Huber;Andrew K. Shiau;Alex Kelly;Suzana T. Cunha Lima;T. Scanlan;J. Apriletti;John D. Baxter;B. West;R. Fletterick
中科院分区：
文献类型：
--
作者：
R. Wagner;B. R. Huber;Andrew K. Shiau;Alex Kelly;Suzana T. Cunha Lima;T. Scanlan;J. Apriletti;John D. Baxter;B. West;R. Fletterick
单独的基因编码甲状腺激素受体亚型 TRalpha (NR1A1) 和 TRbeta (NR1A2)。每种物质的产物都有助于激素作用，但不同亚型的组织分布和生理反应不同。体内区分这些亚型的化合物可用于治疗重要的医学问题，例如肥胖和高胆固醇血症。我们之前确定了大鼠 (r) TRalpha 配体结合域 (LBD) 的晶体结构。在本研究中，我们确定了与附加配体 Triac（3,5,3'-三碘甲状腺乙酸）形成的复合物中 rTRalpha LBD 的晶体结构，以及与 Triac 或 TRbeta 选择性化合物 GC-1 形成的复合物中人 (h) TRbeta 受体 LBD 的两种晶体结构 [3,5-二甲基-4-(4'-羟基-3'-异丙基苄基)-苯氧基乙酸]。 rTRalpha 和 hTRbeta LBD 显示出密切的结构相似性。然而，hTRbeta 结构延伸至 DNA 结合域并允许定义仅由三个氨基酸组成的结构“铰链”区域。两种 TR 亚型在螺旋 1 和 3 之间的环上有所不同，这可能会影响配体识别以及配体在结合共激活子和辅阻遏物中的作用。这两种亚型的差异还在于激素结合袋中的一个氨基酸残基，即 Asn (TRbeta) 与 Ser (TRalpha)。对其中亚型特异性残基交换的 TR 的研究表明，大部分结合选择性源自这种氨基酸差异。 TRbeta 受体极性区域的灵活性，与 1-碳位置化学基团的差异识别相结合，似乎可以稳定 GC-1 的复合物，并有助于其 β 选择性。这些结果提出了一种开发亚型特异性化合物的策略，涉及 1 位配体的修饰。
Separate genes encode thyroid hormone receptor subtypes TRalpha (NR1A1) and TRbeta (NR1A2). Products from each of these contribute to hormone action, but the subtypes differ in tissue distribution and physiological response. Compounds that discriminate between these subtypes in vivo may be useful in treating important medical problems such as obesity and hypercholesterolemia. We previously determined the crystal structure of the rat (r) TRalpha ligand-binding domain (LBD). In the present study, we determined the crystal structure of the rTRalpha LBD in a complex with an additional ligand, Triac (3,5, 3'-triiodothyroacetic acid), and two crystal structures of the human (h) TRbeta receptor LBD in a complex with either Triac or a TRbeta-selective compound, GC-1 [3,5-dimethyl-4-(4'-hydroy-3'-isopropylbenzyl)-phenoxy acetic acid]. The rTRalpha and hTRbeta LBDs show close structural similarity. However, the hTRbeta structures extend into the DNA-binding domain and allow definition of a structural "hinge" region of only three amino acids. The two TR subtypes differ in the loop between helices 1 and 3, which could affect both ligand recognition and the effects of ligand in binding coactivators and corepressors. The two subtypes also differ in a single amino acid residue in the hormone-binding pocket, Asn (TRbeta) for Ser (TRalpha). Studies here with TRs in which the subtype-specific residue is exchanged suggest that most of the selectivity in binding derives from this amino acid difference. The flexibility of the polar region in the TRbeta receptor, combined with differential recognition of the chemical group at the 1-carbon position, seems to stabilize the complex with GC-1 and contribute to its beta-selectivity. These results suggest a strategy for development of subtype-specific compounds involving modifications of the ligand at the 1-position.