5C4T
Identification of a Novel Allosteric Binding Site for RORgt Inhibitors
Summary for 5C4T
| Entry DOI | 10.2210/pdb5c4t/pdb |
| Related | 5C4O 5C4S 5C4U |
| Descriptor | Nuclear receptor ROR-gamma, (1S)-4-{1-[2-chloro-6-(trifluoromethyl)benzoyl]-4-fluoro-1H-indazol-3-yl}-1-methylcyclohex-3-ene-1-carboxylic acid, SULFATE ION, ... (5 entities in total) |
| Functional Keywords | allosteric, inhibitor, transcription-transcription inhibitor complex, transcription/transcription inhibitor |
| Biological source | Homo sapiens (Human) |
| Cellular location | Nucleus : P51449 |
| Total number of polymer chains | 1 |
| Total formula weight | 29502.29 |
| Authors | Parthasarathy, G.,Soisson, S. (deposition date: 2015-06-18, release date: 2015-12-16, Last modification date: 2024-03-06) |
| Primary citation | Scheepstra, M.,Leysen, S.,van Almen, G.C.,Miller, J.R.,Piesvaux, J.,Kutilek, V.,van Eenennaam, H.,Zhang, H.,Barr, K.,Nagpal, S.,Soisson, S.M.,Kornienko, M.,Wiley, K.,Elsen, N.,Sharma, S.,Correll, C.C.,Trotter, B.W.,van der Stelt, M.,Oubrie, A.,Ottmann, C.,Parthasarathy, G.,Brunsveld, L. Identification of an allosteric binding site for ROR gamma t inhibition. Nat Commun, 6:8833-8833, 2015 Cited by PubMed Abstract: RORγt 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 RORγt. Co-crystallization of the ligand binding domain (LBD) of RORγt 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 RORγt 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. RORγt function is thus antagonized in a manner molecularly distinct from that of previously described orthosteric RORγt ligands. This brings forward an approach to target RORγt 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. PubMed: 26640126DOI: 10.1038/ncomms9833 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.77 Å) |
Structure validation
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