4YPQ: Crystal Structure Of The Ror(gamma)t Ligand Binding Domain In Complex With 4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-1h-indazol-3-yl) Benzoic Acid

RORgammat is critical for the differentiation and proliferation of Th17 cells associated with several chronic autoimmune diseases. We report the discovery of a novel allosteric binding site on the nuclear receptor RORgammat. Co-crystallization of the ligand binding domain (LBD) of RORgammat with a series of small-molecule antagonists demonstrates occupancy of a previously unreported allosteric binding pocket. Binding at this non-canonical site induces an unprecedented conformational reorientation of helix 12 in the RORgammat LBD, which blocks cofactor binding. The functional consequence of this allosteric ligand-mediated conformation is inhibition of function as evidenced by both biochemical and cellular studies. RORgammat function is thus antagonized in a manner molecularly distinct from that of previously described orthosteric RORgammat ligands. This brings forward an approach to target RORgammat for the treatment of Th17-mediated autoimmune diseases. The elucidation of an unprecedented modality of pharmacological antagonism establishes a mechanism for modulation of nuclear receptors.
PDB ID: 4YPQDownload
MMDB ID: 135002
PDB Deposition Date: 2015/3/13
Updated in MMDB: 2015/12
Experimental Method:
x-ray diffraction
Resolution: 2.32  Å
Source Organism:
Similar Structures:
Biological Unit for 4YPQ: monomeric; determined by author and by software (PISA)
Molecular Components in 4YPQ
Label Count Molecule
Protein (1 molecule)
Nuclear Receptor Ror-gamma(Gene symbol: RORC)
Molecule annotation
Chemicals (2 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB