Ternary crystal structure of human ROR\u03b3 ligand-binding-domain, an inhibitor and corepressor peptide provides a new insight into corepressor interaction

Scott Thacher,Yoshiaki Katsuda,Tsuyoshi Adachi,Katsuya Maeda,Masayuki Kotoku,Masato Noguchi,Shintaro Hirashima,Akihiro Nomura,Keishi Yamaguchi,Takayuki Yamaguchi,Satoki Doi,Paul Crowe,Makoto Shiozaki,Haiyan Tao,Kazuyuki Hirata

doi:10.1038/s41598-018-35783-9

Scott Thacher, Yoshiaki Katsuda + Show 13 more

Open Access

https://doi.org/10.1038/s41598-018-35783-9

Copy DOI

Abstract

Retinoic acid-related orphan receptor gamma (RORγ) plays pivotal roles in autoimmune diseases by controlling the lineage of interleukin 17 (IL-17)-producing CD4+ T cells (Th17 cells). Structure-based drug design has proven fruitful in the development of inhibitors targeting the ligand binding domain (LBD) of RORγ. Here, we present the crystal structure of a novel RORγ inhibitor co-complex, in the presence of a corepressor (CoR) peptide. This ternary complex with compound T reveals the structural basis for an inhibitory mechanism different from the previously reported inverse agonist. Compared to the inverse agonist, compound T induces about 2 Å shift of helix 5 (H5) backbone and side-chain conformational changes of Met365 on H5. These conformational changes correlate to reduced CoR peptide binding to RORγ-LBD in the presence of compound T, which suggests that the shift of H5 is responsible. This crystal structure analysis will provide useful information for the development of novel and efficacious drugs for autoimmune disorders.

Highlights

Retinoic acid-related orphan receptor gamma (RORγ) plays pivotal roles in autoimmune diseases by controlling the lineage of interleukin 17 (IL-17)-producing CD4+ T cells (Th17 cells)
T helper 17 (Th17) cells and the cytokine production play a pivotal role in autoimmune disease pathology in psoriasis, inflammatory bowel disease, rheumatoid arthritis and multiple sclerosis[1,2,3,4,5,6]
The CoR peptide-recruiting activity of rockogenin was not detected in dual FRET assay because of its low inhibitory activity, but the ternary complex was obtained in previous report[12]

Summary

Introduction

Retinoic acid-related orphan receptor gamma (RORγ) plays pivotal roles in autoimmune diseases by controlling the lineage of interleukin 17 (IL-17)-producing CD4+ T cells (Th17 cells). We present the crystal structure of a novel RORγ inhibitor co-complex, in the presence of a corepressor (CoR) peptide This ternary complex with compound T reveals the structural basis for an inhibitory mechanism different from the previously reported inverse agonist. Compared to the inverse agonist, compound T induces about 2 Å shift of helix 5 (H5) backbone and side-chain conformational changes of Met[365] on H5 These conformational changes correlate to reduced CoR peptide binding to RORγ-LBD in the presence of compound T, which suggests that the shift of H5 is responsible. This crystal structure analysis will provide useful information for the development of novel and efficacious drugs for autoimmune disorders.

Methods

Results

Conclusion