6NWT
RORgamma Ligand Binding Domain
Summary for 6NWT
| Entry DOI | 10.2210/pdb6nwt/pdb |
| Descriptor | Nuclear receptor ROR-gamma, 1,1,1,3,3,3-hexafluoro-2-[2-fluoro-4'-({4-[(pyridin-4-yl)methyl]piperazin-1-yl}methyl)[1,1'-biphenyl]-4-yl]propan-2-ol (3 entities in total) |
| Functional Keywords | orphan nuclear receptor, synthetic modulator, chemical probe, nuclear protein |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 58012.91 |
| Authors | Strutzenberg, T.S.,Park, H.,Griffin, P.R. (deposition date: 2019-02-07, release date: 2019-07-10, Last modification date: 2023-10-11) |
| Primary citation | Strutzenberg, T.S.,Garcia-Ordonez, R.D.,Novick, S.J.,Park, H.,Chang, M.R.,Doebellin, C.,He, Y.,Patouret, R.,Kamenecka, T.M.,Griffin, P.R. HDX-MS reveals structural determinants for ROR gamma hyperactivation by synthetic agonists. Elife, 8:-, 2019 Cited by PubMed Abstract: Members of the nuclear receptor (NR) superfamily regulate both physiological and pathophysiological processes ranging from development and metabolism to inflammation and cancer. Synthetic small molecules targeting NRs are often deployed as therapeutics to correct aberrant NR signaling or as chemical probes to explore the role of the receptor in physiology. Nearly half of NRs do not have specific cognate ligands (termed orphan NRs) and it's unclear if they possess ligand dependent activities. Here we demonstrate that ligand-dependent action of the orphan RORγ can be defined by selectively disrupting putative endogenous-but not synthetic-ligand binding. Furthermore, the characterization of a library of RORγ modulators reveals that structural dynamics of the receptor assessed by HDX-MS correlate with activity in biochemical and cell-based assays. These findings, corroborated with X-ray co-crystallography and site-directed mutagenesis, collectively reveal the structural determinants of RORγ activation, which is critical for designing RORγ agonists for cancer immunotherapy. PubMed: 31172947DOI: 10.7554/eLife.47172 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.35 Å) |
Structure validation
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