6nwt
RORgamma Ligand Binding DomainRORgamma Ligand Binding Domain
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 PubMedMembers 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 RORgamma can be defined by selectively disrupting putative endogenous-but not synthetic-ligand binding. Furthermore, the characterization of a library of RORgamma 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 RORgamma activation, which is critical for designing RORgamma agonists for cancer immunotherapy. HDX-MS reveals structural determinants for RORgamma hyperactivation by synthetic agonists.,Strutzenberg TS, Garcia-Ordonez RD, Novick SJ, Park H, Chang MR, Doebellin C, He Y, Patouret R, Kamenecka TM, Griffin PR Elife. 2019 Jun 7;8. pii: 47172. doi: 10.7554/eLife.47172. PMID:31172947[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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