RORγ Structural Plasticity and Druggability

Retinoic acid receptor-related orphan receptor gamma (ROR gamma) is a transcription factor regulating the expression of the pro-inflammatory cytokine IL-17 in human T helper 17 (Th17) cells. Activating ROR gamma can induce multiple IL-17-mediated autoimmune diseases but may also be useful for anticancer therapy. Its deep immunological functions make ROR(sic) an attractive drug target. Over 100 crystal structures have been published describing atomic interactions between ROR(sic) and agonists and inverse agonists. In this review, we focus on the role of dynamic properties and plasticity of the ROR(sic) orthosteric and allosteric binding sites by examining structural information from crystal structures and simulated models. We discuss the possible influences of allosteric ligands on the orthosteric binding site. We find that high structural plasticity favors the druggability of RORE, especially for allosteric ligands.