Figure 1: Co-crystal structure of RORγt with MRL-871.
From: Identification of an allosteric binding site for RORγt inhibition
(a) Chemical structures of a representative orthosteric ligand T0901317 (ref. 27), binding to the canonical site of NRs, and indazoles MRL-871, MRL-058 and MRL-003. (b) Zoomed-in view of MRL-871 in the novel allosteric-binding pocket of RORγt formed by helices 4, 5, 11 and 12. MRL-871 shown as orange sticks in the electron density. The RORγt residues involved in hydrophobic interactions and hydrogen bonding are shown as white and green sticks, respectively. (c) Superposition of RORγt (blue) in complex with orthosteric ligand T0901317 shown in red (PDB ID 4NB6)26 and RORγt (green) in complex with MRL-871, shown in orange. MRL-871 (orange) sits in a new allosteric pocket in direct contact with H12 inducing its repositioning. Orthosteric ligand T0901317 destabilizes H12, which is therefore not visible in the blue structure. (d) A two-dimensional plot showing the interactions between MRL-871 and the surrounding amino acids.
