 |
PDBsum entry 5vb7
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Transcription
|
PDB id
|
|
|
|
5vb7
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Structural studies unravel the active conformation of apo rorγt nuclear receptor and a common inverse agonism of two diverse classes of rorγt inhibitors.
|
|
|
Authors
|
|
X.Li,
M.Anderson,
D.Collin,
I.Muegge,
J.Wan,
D.Brennan,
S.Kugler,
D.Terenzio,
C.Kennedy,
S.Lin,
M.E.Labadia,
B.Cook,
R.Hughes,
N.A.Farrow.
|
|
|
Ref.
|
|
J Biol Chem, 2017,
292,
11618-11630.
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
The nuclear receptor retinoid acid receptor-related orphan receptor γt (RORγt)
is a master regulator of the Th17/IL-17 pathway that plays crucial roles in the
pathogenesis of autoimmunity. RORγt 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
RORγt. Here, we report the crystal structures for the ligand-binding domain of
RORγt in both apo and ligand-bound states. We show that apo RORγt adopts an
active conformation capable of recruiting coactivator peptides and present a
detailed analysis of the structural determinants that stabilize helix 12 (H12)
of RORγt in the active state in the absence of a ligand. The structures of
ligand-bound RORγt reveal that binding of the inverse agonists disrupts
critical interactions that stabilize H12. This destabilizing effect is supported
byab initiocalculations and experimentally by a normalized
crystallographic B-factor analysis. Of note, the H12 destabilization in the
active state shifts the conformational equilibrium of RORγt 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.
|
|
|
|
|
|
|
