Wagner R L, Huber B R, Shiau A K, Kelly A, Cunha Lima S T, Scanlan T S, Apriletti J W, Baxter J D, West B L, Fletterick R J
Department of Biochemistry, University of California, San Francisco, California 94143, USA.
Mol Endocrinol. 2001 Mar;15(3):398-410. doi: 10.1210/mend.15.3.0608.
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.
不同的基因编码甲状腺激素受体亚型TRα（NR1A1）和TRβ（NR1A2）。这些亚型的产物都参与激素作用，但在组织分布和生理反应方面存在差异。能够在体内区分这些亚型的化合物可能有助于治疗肥胖症和高胆固醇血症等重要医学问题。我们之前确定了大鼠（r）TRα配体结合结构域（LBD）的晶体结构。在本研究中，我们确定了rTRα LBD与另一种配体3,5,3'-三碘甲状腺乙酸（Triac）形成的复合物的晶体结构，以及人（h）TRβ受体LBD与Triac或TRβ选择性化合物GC-1 [3,5-二甲基-4-(4'-羟基-3'-异丙基苄基)-苯氧基乙酸]形成的复合物的两种晶体结构。rTRα和hTRβ LBD显示出密切的结构相似性。然而，hTRβ结构延伸至DNA结合结构域，并确定了一个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之间的环上存在差异，这可能会影响配体识别以及配体与共激活因子和共抑制因子结合的效果。两种亚型在激素结合口袋中的一个氨基酸残基也不同，TRβ为Asn，TRα为Ser。此处对交换了亚型特异性残基TR的研究表明，结合的大部分选择性源于这种氨基酸差异。TRβ受体极性区域的灵活性，加上对1-碳位置化学基团的差异识别，似乎稳定了与GC-1的复合物并促成其β选择性。这些结果提示了一种开发亚型特异性化合物的策略，即对配体的1-位进行修饰。
