Noguchi Masato, Nomura Akihiro, Murase Ken, Doi Satoki, Yamaguchi Keishi, Hirata Kazuyuki, Shiozaki Makoto, Hirashima Shintaro, Kotoku Masayuki, Yamaguchi Takayuki, Katsuda Yoshiaki, Steensma Ruo, Li Xioalin, Tao Haiyan, Tse Bruno, Fenn Morgan, Babine Robert, Bradley Erin, Crowe Paul, Thacher Scott, Adachi Tsuyoshi, Kamada Masafumi
Pharmaceutical Frontier Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-13-2, Fukuura, Kanazawa-Ku, Yokohama, Kanagawa, 236-0004, Japan.
Chemical Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
Genes Cells. 2017 Jun;22(6):535-551. doi: 10.1111/gtc.12494. Epub 2017 May 11.
Retinoid-related orphan receptor gamma (RORγ) directly controls the differentiation of Th17 cell and the production of interleukin-17, which plays an integral role in autoimmune diseases. To obtain insight into RORγ, we have determined the first crystal structure of a ternary complex containing RORγ ligand-binding domain (LBD) bound with a novel synthetic inhibitor and a repressor peptide, 22-mer peptide from silencing mediator of retinoic acid and thyroid hormone receptor (SMRT). Comparison of a binary complex of nonliganded (apo) RORγ-LBD with a nuclear receptor co-activator (NCoA-1) peptide has shown that our inhibitor displays a unique mechanism different from those caused by natural inhibitor, ursolic acid (UA). The compound unprecedentedly induces indirect disruption of a hydrogen bond between His479 on helix 11 (H11) and Tyr502 on H12, which is crucial for active conformation. This crystallographic study will allow us to develop novel synthetic compounds for autoimmune disease therapy.
维甲酸相关孤儿受体γ（RORγ）直接控制Th17细胞的分化和白细胞介素-17的产生，白细胞介素-17在自身免疫性疾病中起着不可或缺的作用。为了深入了解RORγ，我们确定了一种三元复合物的首个晶体结构，该复合物包含与一种新型合成抑制剂和一种阻遏肽结合的RORγ配体结合域（LBD），该阻遏肽是来自维甲酸和甲状腺激素受体沉默介质（SMRT）的22肽。非配体（无apo）RORγ-LBD与核受体共激活因子（NCoA-1）肽的二元复合物比较表明，我们的抑制剂显示出一种与天然抑制剂熊果酸（UA）不同的独特机制。该化合物前所未有的诱导螺旋11（H11）上的His479与H12上的Tyr502之间氢键的间接破坏，这对于活性构象至关重要。这项晶体学研究将使我们能够开发用于自身免疫性疾病治疗的新型合成化合物。
