4S15
Crystal structure of the orphan nuclear receptor RORalpha ligand-binding domain in complex with 4alpha-caboxyl, 4beta-methyl-zymosterol (4ACD8)
Summary for 4S15
| Entry DOI | 10.2210/pdb4s15/pdb |
| Related | 4S14 |
| Descriptor | Nuclear receptor ROR-alpha, Nuclear receptor-interacting protein 1, (3beta,4alpha,5beta,14beta)-3-hydroxy-4-methylcholesta-8,24-diene-4-carboxylic acid, ... (5 entities in total) |
| Functional Keywords | transcription factor, transcription |
| Biological source | Homo sapiens (human) More |
| Cellular location | Nucleus : P35398 P48552 |
| Total number of polymer chains | 4 |
| Total formula weight | 63521.81 |
| Authors | Huang, P.,Santori, F.R.,Littman, D.R.,Rastinejad, F. (deposition date: 2015-01-08, release date: 2015-02-11, Last modification date: 2024-02-28) |
| Primary citation | Santori, F.R.,Huang, P.,van de Pavert, S.A.,Douglass, E.F.,Leaver, D.J.,Haubrich, B.A.,Keber, R.,Lorbek, G.,Konijn, T.,Rosales, B.N.,Rozman, D.,Horvat, S.,Rahier, A.,Mebius, R.E.,Rastinejad, F.,Nes, W.D.,Littman, D.R. Identification of Natural ROR gamma Ligands that Regulate the Development of Lymphoid Cells. Cell Metab, 21:286-297, 2015 Cited by PubMed Abstract: Mice deficient in the nuclear hormone receptor RORγt have defective development of thymocytes, lymphoid organs, Th17 cells, and type 3 innate lymphoid cells. RORγt binds to oxysterols derived from cholesterol catabolism, but it is not clear whether these are its natural ligands. Here, we show that sterol lipids are necessary and sufficient to drive RORγt-dependent transcription. We combined overexpression, RNAi, and genetic deletion of metabolic enzymes to study RORγ-dependent transcription. Our results are consistent with the RORγt ligand(s) being a cholesterol biosynthetic intermediate (CBI) downstream of lanosterol and upstream of zymosterol. Analysis of lipids bound to RORγ identified molecules with molecular weights consistent with CBIs. Furthermore, CBIs stabilized the RORγ ligand-binding domain and induced coactivator recruitment. Genetic deletion of metabolic enzymes upstream of the RORγt-ligand(s) affected the development of lymph nodes and Th17 cells. Our data suggest that CBIs play a role in lymphocyte development potentially through regulation of RORγt. PubMed: 25651181DOI: 10.1016/j.cmet.2015.01.004 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.897 Å) |
Structure validation
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