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

Autor:	Masayuki Kotoku, Makoto Shiozaki, Akihiro Nomura, Takayuki Yamaguchi, Scott Thacher, Haiyan Tao, Paul Crowe, Satoki Doi, Keishi Yamaguchi, Shintaro Hirashima, Katsuya Maeda, Masato Noguchi, Tsuyoshi Adachi, Yoshiaki Katsuda, Kazuyuki Hirata
Jazyk:	angličtina
Rok vydání:	2018
Předmět:	0301 basic medicine Stereochemistry lcsh:Medicine Peptide binding Peptide Plasma protein binding Article Autoimmune Diseases Structure-Activity Relationship 03 medical and health sciences 0302 clinical medicine Protein Domains Humans Structure–activity relationship Inverse agonist lcsh:Science Ternary complex Orphan receptor chemistry.chemical_classification Multidisciplinary Interleukin-17 lcsh:R Nuclear Receptor Subfamily 1 Group F Member 3 030104 developmental biology chemistry 030220 oncology & carcinogenesis Th17 Cells lcsh:Q Peptides Co-Repressor Proteins Corepressor Protein Binding
Zdroj:	Scientific Reports, Vol 8, Iss 1, Pp 1-8 (2018) Scientific Reports
ISSN:	2045-2322
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::cd8a3773ea748399c2e67ba680c3af4f http://link.springer.com/article/10.1038/s41598-018-35783-9 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
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