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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. © 2017 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.

Citation

Masato Noguchi, Akihiro Nomura, Ken Murase, Satoki Doi, Keishi Yamaguchi, Kazuyuki Hirata, Makoto Shiozaki, Shintaro Hirashima, Masayuki Kotoku, Takayuki Yamaguchi, Yoshiaki Katsuda, Ruo Steensma, Xioalin Li, Haiyan Tao, Bruno Tse, Morgan Fenn, Robert Babine, Erin Bradley, Paul Crowe, Scott Thacher, Tsuyoshi Adachi, Masafumi Kamada. Ternary complex of human RORγ ligand-binding domain, inverse agonist and SMRT peptide shows a unique mechanism of corepressor recruitment. Genes to cells : devoted to molecular & cellular mechanisms. 2017 Jun;22(6):535-551

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PMID: 28493531

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