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

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

SUBMITTER: Noguchi M 

PROVIDER: S-EPMC6255837 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature