The nuclear receptor RORgt (retinoid acid-related orphan receptor gt) is a central regulator of the IL17/IL23 pathway that plays crucial roles in the pathogenesis of autoimmunity. Therefore RORgt has emerged in recent years as a highly promising target for a number of autoimmune diseases. As an orphan nuclear receptor, the endogenous ligand for RORgt is unknown, and RORgt is believed to be constitutively active. Through high throughput screening we have identified novel inverse agonists for RORgt. Here we report the crystal structures for the ligand binding domain of RORgt in both ligand-free and ligand-bound states. We show that the apo RORgt adopts a fully active conformation. The structural determinants that stabilize Helix12 of RORgt in the active state in the absence of a ligand will be discussed. Interestingly the crystal structures of ligand-bound RORgt reveal that binding of our inverse agonists disrupts these critical interactions that stabilize Helix12. This destabilizing effect is supported by a normalized crystallographic B-factor analysis, which reveals the inverse agonists bound RORgt has elevated B-factors in the Helix12 region compared to its ligand-free form. The destabilization of Helix12 in the active state shifts the conformational equilibrium of RORgt towards the inactive state(s), which underlies the molecular mechanism of action for the inverse agonists reported here.

Structural basis for the inverse agonism of novel RORγt Inhibitors

249th National Meeting (2015)

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