5vb7

Publication Abstract from PubMed

The nuclear receptor retinoid acid receptor-related orphan receptor gammat (RORgammat) is a master regulator of the Th17/IL-17 pathway that plays crucial roles in the pathogenesis of autoimmunity. RORgammat has recently emerged as a highly promising target for treatment of a number of autoimmune diseases. Through high-throughput screening, we previously identified several classes of inverse agonists for RORgammat. Here, we report the crystal structures for the ligand-binding domain of RORgammat in both apo and ligand-bound states. We show that apo RORgammat adopts an active conformation capable of recruiting coactivator peptides and present a detailed analysis of the structural determinants that stabilize helix 12 (H12) of RORgammat in the active state in the absence of a ligand. The structures of ligand-bound RORgammat reveal that binding of the inverse agonists disrupts critical interactions that stabilize H12. This destabilizing effect is supported by ab initio calculations and experimentally by a normalized crystallographic B-factor analysis. Of note, the H12 destabilization in the active state shifts the conformational equilibrium of RORgammat toward an inactive state, which underlies the molecular mechanism of action for the inverse agonists reported here. Our findings highlight that nuclear receptor structure and function are dictated by a dynamic conformational equilibrium and that subtle changes in ligand structures can shift this equilibrium in opposite directions, leading to a functional switch from agonists to inverse agonists.

Structural studies unravel the active conformation of apo RORgammat nuclear receptor and a common inverse agonism of two diverse classes of RORgammat inhibitors.,Li X, Anderson M, Collin D, Muegge I, Wan J, Brennan D, Kugler S, Terenzio D, Kennedy C, Lin S, Labadia ME, Cook B, Hughes R, Farrow NA J Biol Chem. 2017 Jul 14;292(28):11618-11630. doi: 10.1074/jbc.M117.789024. Epub , 2017 May 25. PMID:28546429^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.