Agonist Lock Touched and Untouched Retinoic Acid Receptor-Related Orphan Receptor-γt (RORγt) Inverse Agonists: Classification Based on the Molecular Mechanisms of Action

Retinoic acid receptor-related orphan receptor-gamma-t (RORγt) is a potential drug target for autoimmune diseases with a clear biological mechanism in the Th17/IL-17 pathway. The "agonist lock", which is formed by residues His479-Tyr502-Phe506 in RORγt, makes H12 tightly contact H11 in a suitable conformation for coactivator binding and, thus, is related to RORγt transcriptional activation. The inverse agonism of RORγt is complex because not all RORγt inverse agonists directly break the agonist lock to interfere with coactivator recruitment and the transcription of RORγt. Here, we analyze the complex structures, binding modes, and biological activities of various RORγt inverse agonists and classify them as "agonist lock touched" and "agonist lock untouched" RORγt inverse agonists according to whether they infringe on the agonist lock directly or not. We aim at providing a comprehensive review and insights into drug discovery of RORγt inverse agonists.