Agonist Lock Touched and Untouched Retinoic Acid Receptor-Related Orphan Receptor-γt (RORγt) Inverse Agonists: Classification Based on the Molecular Mechanisms of Action
Agonist Lock Touched and Untouched Retinoic Acid Receptor-Related Orphan Receptor-γt (RORγt) Inverse Agonists: Classification Based on the Molecular Mechanisms of Action
复制标题
激动剂锁定接触和未接触视黄酸受体相关孤儿受体-γt (RORγt) 反向激动剂：基于分子作用机制的分类
DOI：
10.1021/acs.jmedchem.0c02178
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发表时间：
2021
影响因子：
7.3
通讯作者：
Yonghui Wang
中科院分区：
文献类型：
--
作者：
Nannan Sun;Qiong Xie;Yongjun Dang;Yonghui Wang
视黄酸受体相关孤儿受体-γ-t(RoR-γ-t)是治疗自身免疫性疾病的潜在药物靶点，在Th17/IL-17途径中有明确的生物学机制。由RoRγt中的His479-Tyr502-Phe506残基形成的“激动剂锁”，使H12以合适的构象与H11紧密接触，与共激活物结合，从而与RoRγt转录激活有关。由于并不是所有的RoRγt反向激动剂都直接破坏激动剂的锁来干扰辅活剂的募集和RoRγt的转录，所以RoRγt的反向激动剂的作用是复杂的。本文分析了各种RoRγt反向激动剂的复杂结构、结合方式和生物活性，并根据它们是否直接侵犯了激动剂的锁，将其分为“已触及的激动剂锁”和“未触及的激动剂锁”。我们的目的是对RoRγt反向激动剂的药物发现提供全面的综述和见解。
Retinoic acid receptor-related orphan receptor-gamma-t (RORγt) is a potential drug target for autoimmune diseases with a clear biological mechanism in the Th17/IL-17 pathway. The “agonist lock”, which is formed by residues His479-Tyr502-Phe506 in RORγt, makes H12 tightly contact H11 in a suitable conformation for coactivator binding and, thus, is related to RORγt transcriptional activation. The inverse agonism of RORγt is complex because not all RORγt inverse agonists directly break the agonist lock to interfere with coactivator recruitment and the transcription of RORγt. Here, we analyze the complex structures, binding modes, and biological activities of various RORγt inverse agonists and classify them as “agonist lock touched” and “agonist lock untouched” RORγt inverse agonists according to whether they infringe on the agonist lock directly or not. We aim at providing a comprehensive review and insights into drug discovery of RORγt inverse agonists.