HDX-MS reveals structural determinants for RORγ hyperactivation by synthetic agonists.
biochemistry
chemical biology
human
hydrogen-deuterium exchange
ligand activation
nuclear receptors
Journal
eLife
ISSN: 2050-084X
Titre abrégé: Elife
Pays: England
ID NLM: 101579614
Informations de publication
Date de publication:
07 06 2019
07 06 2019
Historique:
received:
27
03
2019
accepted:
01
06
2019
pubmed:
8
6
2019
medline:
23
2
2020
entrez:
8
6
2019
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 31172947
doi: 10.7554/eLife.47172
pii: 47172
pmc: PMC6579513
doi:
pii:
Substances chimiques
Ligands
0
Nuclear Receptor Subfamily 1, Group F, Member 3
0
Banques de données
figshare
['10.6084/m9.figshare.8230685']
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2019, Strutzenberg et al.
Déclaration de conflit d'intérêts
TS, RG, SN, HP, MC, CD, YH, RP, TK, PG No competing interests declared
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