Nuclear receptors (NRs) are high-interest targets in drug discovery because of their involvement in numerous biological processes and diseases. Classically, NRs are targeted via their hydrophobic, orthosteric pocket. Although successful, this approach comes with challenges, including off-target effects due to lack of selectivity. Allosteric modulation of NR activity constitutes a promising pharmacological strategy. The retinoic acid receptor-related orphan receptor-γt (RORγt) is a constitutively active NR that positively regulates the expression of interleukin-17 in T helper 17 cells. Inhibiting this process is an emerging strategy for managing autoimmune diseases. Recently, an allosteric binding pocket in the C-terminal region of the ligand-binding domain (LBD) of RORγt was discovered that is amenable to small-molecule drug discovery. Compounds binding this pocket induce a reorientation of helix 12, thereby preventing coactivator recruitment. Therefore, inverse agonists binding this site with high affinity are actively being pursued. To elucidate the pocket formation mechanism, verify the uniqueness of this pocket, and substantiate the relevance of targeting this site, here we identified the key characteristics of the RORγt allosteric region. We evaluated the effects of substitutions in the LBD on coactivator, orthosteric, and allosteric ligand binding. We found that two molecular elements unique to RORγt, the length of helix 11′ and a Gln-487 residue, are crucial for the formation of the allosteric pocket. The unique combination of elements present in RORγt suggests a high potential for subtype-selective targeting of this NR to more effectively treat patients with autoimmune diseases.

中文翻译：

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孤儿核受体 RORγt 独特变构结合位点的分子决定因素的描述。


核受体 (NR) 是药物发现中备受关注的目标，因为它们参与许多生物过程和疾病。传统上，NR 通过其疏水性正构口袋进行靶向。尽管成功，但这种方法也面临着挑战，包括由于缺乏选择性而导致的脱靶效应。 NR 活性的变构调节是一种有前途的药理学策略。视黄酸受体相关孤儿受体-γt (RORγt) 是一种组成型活性 NR，可正向调节 T 辅助 17 细胞中白细胞介素 17 的表达。抑制这一过程是治疗自身免疫性疾病的一种新兴策略。最近，在 RORγt 配体结合结构域 (LBD) C 端区域发现了一个变构结合口袋，适合小分子药物发现。结合该口袋的化合物诱导螺旋 12 的重新定向，从而防止共激活剂募集。因此，正在积极寻找以高亲和力结合该位点的反向激动剂。为了阐明口袋形成机制，验证该口袋的独特性，并证实靶向该位点的相关性，我们确定了 RORγt 变构区域的关键特征。我们评估了 LBD 中的取代对共激活剂、正构和变构配体结合的影响。我们发现 RORγt 特有的两个分子元件，即 11' 螺旋长度和 Gln-487 残基，对于变构袋的形成至关重要。 RORγt 中存在的独特元素组合表明该 NR 的亚型选择性靶向具有很高的潜力，可以更有效地治疗患有自身免疫性疾病的患者。