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T-helper cells that produce interleukin-17 (T_H17 cells) are a recently identified CD4⁺ T-cell subset with characterized pathological roles in autoimmune diseases^,,. The nuclear receptors retinoic-acid-receptor-related orphan receptors α and γt (RORα and RORγt, respectively) have indispensible roles in the development of this cell type^,,,. Here we present SR1001, a high-affinity synthetic ligand—the first in a new class of compound—that is specific to both RORα and RORγt and which inhibits T_H17 cell differentiation and function. SR1001 binds specifically to the ligand-binding domains of RORα and RORγt, inducing a conformational change within the ligand-binding domain that encompasses the repositioning of helix 12 and leads to diminished affinity for co-activators and increased affinity for co-repressors, resulting in suppression of the receptors’ transcriptional activity. SR1001 inhibited the development of murine …