4s14
From Proteopedia
Crystal structure of the orphan nuclear receptor RORgamma ligand-binding domain in complex with 4alpha-caboxyl, 4beta-methyl-zymosterol (4ACD8)
Structural highlights
FunctionRORG_HUMAN Possible nuclear receptor for hydroxycholesterols, the binding of which strongly promotes coactivators recruitment. Essential for thymopoiesis and the development of several secondary lymphoid tissues, including lymph nodes. Involved in lineage specification of uncommitted CD4(+) T-helper cells into Th17 cells. Regulate the expression of several components of the circadian clock. Publication Abstract from PubMedMice deficient in the nuclear hormone receptor RORgammat have defective development of thymocytes, lymphoid organs, Th17 cells, and type 3 innate lymphoid cells. RORgammat 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 RORgammat-dependent transcription. We combined overexpression, RNAi, and genetic deletion of metabolic enzymes to study RORgamma-dependent transcription. Our results are consistent with the RORgammat ligand(s) being a cholesterol biosynthetic intermediate (CBI) downstream of lanosterol and upstream of zymosterol. Analysis of lipids bound to RORgamma identified molecules with molecular weights consistent with CBIs. Furthermore, CBIs stabilized the RORgamma ligand-binding domain and induced coactivator recruitment. Genetic deletion of metabolic enzymes upstream of the RORgammat-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 RORgammat. Identification of Natural RORgamma Ligands that Regulate the Development of Lymphoid Cells.,Santori FR, Huang P, van de Pavert SA, Douglass EF Jr, Leaver DJ, Haubrich BA, Keber R, Lorbek G, Konijn T, Rosales BN, Rozman D, Horvat S, Rahier A, Mebius RE, Rastinejad F, Nes WD, Littman DR Cell Metab. 2015 Feb 3;21(2):286-97. doi: 10.1016/j.cmet.2015.01.004. PMID:25651181[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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