3b0w
Crystal structure of the orphan nuclear receptor ROR(gamma)t ligand-binding domain in complex with digoxin
Structural highlights
FunctionRORG_HUMAN Possible nuclear receptor for hydroxycholesterols, the binding of which strongly promotes coactivators recruitment. Essential for thymopoiesis and the development of several secondary lymphoid tissues, including lymph nodes. Involved in lineage specification of uncommitted CD4(+) T-helper cells into Th17 cells. Regulate the expression of several components of the circadian clock. Publication Abstract from PubMedThe retinoic acid-related orphan nuclear receptor gammat (RORgammat)/RORgamma2 is well known as a master regulator of interleukin 17 (IL-17)-producing helper T (Th17) cell development. To develop a therapeutic agent against Th17-mediated autoimmune diseases, we screened chemical compounds and successfully found that digoxin inhibited IL-17 production. Further studies revealed that digoxin bound to the ligand binding domain of RORgammat and suppressed Th17 differentiation without affecting Th1 differentiation. To better understand the structural basis for the inhibitory activity of digoxin, we determined the crystal structure of the RORgammat ligand-binding domain in complex with digoxin at 2.2 A resolution. The structure reveals that digoxin binds to the ligand-binding pocket protruding between helices H3 and H11 from the pocket. In addition, digoxin disrupts the key interaction important for the agonistic activity, resulting in preventing the positioning of helix H12 in the active conformation, thus antagonizing coactivator interaction. Functional studies demonstrated that digoxin inhibited RORgammat activity and decreased IL-17 production but not RORalpha activity. Digoxin inhibited IL-17 production in CD4(+) T cells from experimental autoimmune encephalomyelitis mice. Our data indicates that RORgammat is a promising therapeutic target for Th17-derived autoimmune diseases and our structural data will help to design novel RORgammat antagonists. Structural Basis of Digoxin That Antagonizes ROR{gamma}t Receptor Activity and Suppresses Th17 Cell Differentiation and Interleukin (IL)-17 Production.,Fujita-Sato S, Ito S, Isobe T, Ohyama T, Wakabayashi K, Morishita K, Ando O, Isono F J Biol Chem. 2011 Sep 9;286(36):31409-17. Epub 2011 Jul 6. PMID:21733845[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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