Delineation of the molecular determinants of the unique allosteric binding site of the orphan nuclear receptor RORγt.

ABSTRACT: Nuclear receptors (NRs) are high-interest targets in drug discovery because of their involvement in numerous biological processes and diseases. Classically, NRs are targeted via their hydrophobic, orthosteric pocket. Although successful, this approach comes with challenges, including off-target effects due to lack of selectivity. Allosteric modulation of NR activity constitutes a promising pharmacological strategy. The retinoic acid receptor-related orphan receptor-γt (RORγt) is a constitutively active NR that positively regulates the expression of interleukin-17 in T helper 17 cells. Inhibiting this process is an emerging strategy for managing autoimmune diseases. Recently, an allosteric binding pocket in the C-terminal region of the ligand-binding domain (LBD) of RORγt was discovered tha

SUBMITTER: Leijten-van de Gevel IA 

PROVIDER: S-EPMC7335795 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature