Department of Biochemistry and Molecular Biophysics, Kansas State University, Manhattan, KS 66506, USA.
Division of Biology, Kansas State University, Manhattan, KS 66506, USA.
Int J Mol Sci. 2020 Jul 27;21(15):5329. doi: 10.3390/ijms21155329.
Retinoic acid receptor-related orphan receptor γ (RORγ) is a transcription factor regulating the expression of the pro-inflammatory cytokine IL-17 in human T helper 17 (Th17) cells. Activating RORγ can induce multiple IL-17-mediated autoimmune diseases but may also be useful for anticancer therapy. Its deep immunological functions make RORɣ an attractive drug target. Over 100 crystal structures have been published describing atomic interactions between RORɣ and agonists and inverse agonists. In this review, we focus on the role of dynamic properties and plasticity of the RORɣ orthosteric and allosteric binding sites by examining structural information from crystal structures and simulated models. We discuss the possible influences of allosteric ligands on the orthosteric binding site. We find that high structural plasticity favors the druggability of RORɣ, especially for allosteric ligands.
维甲酸相关孤儿受体γ（RORγ）是一种转录因子，可调节人类辅助性 T 细胞 17（Th17）细胞中促炎细胞因子白细胞介素 17（IL-17）的表达。激活 RORγ 可诱导多种由 IL-17 介导的自身免疫性疾病，但也可能对癌症治疗有用。其深入的免疫学功能使其成为一种有吸引力的药物靶点。已经发表了超过 100 个晶体结构，描述了 RORγ 与激动剂和反向激动剂之间的原子相互作用。在这篇综述中，我们通过检查晶体结构和模拟模型中的结构信息，重点关注 RORγ 变构和正位结合位点的动态特性和可塑性。我们讨论了变构配体对正位结合位点的可能影响。我们发现，高结构可塑性有利于 RORγ 的成药性，特别是对于变构配体。
