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Ternary complex of human ROR γ ligand‐binding domain, inverse agonist and SMRT peptide shows a unique mechanism of corepressor recruitment
Author(s) -
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
Publication year - 2017
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1111/gtc.12494
Subject(s) - corepressor , nuclear receptor , orphan receptor , biology , ternary complex , inverse agonist , receptor , peptide , nuclear receptor co repressor 1 , biochemistry , stereochemistry , agonist , microbiology and biotechnology , chemistry , transcription factor , gene , enzyme
Retinoid‐related orphan receptor gamma ( ROR γ) 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 ROR γ, we have determined the first crystal structure of a ternary complex containing ROR γ 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) ROR γ‐ LBD with a nuclear receptor co‐activator ( NC oA‐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.