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Probing the Complex Binding Modes of the PPARγ Partial Agonist 2‑Chloro‑N‑(3-chloro-4-((5-chlorobenzo[d]thiazol-2-yl)thio)phenyl)-4-(trifluoromethyl)benzenesulfonamide (T2384) to Orthosteric and Allosteric Sites with NMR Spectroscopy
dataset
posted on 2016-10-26, 00:00 authored by Travis
S. Hughes, Jinsai Shang, Richard Brust, Ian Mitchelle S. de Vera, Jakob Fuhrmann, Claudia Ruiz, Michael D. Cameron, Theodore M. Kamenecka, Douglas J. KojetinIn
a previous study, a cocrystal structure of PPARγ bound
to 2-chloro-N-(3-chloro-4-((5-chlorobenzo[d]thiazol-2-yl)thio)phenyl)-4-(trifluoromethyl)benzenesulfonamide
(1, T2384) revealed two orthosteric pocket binding modes
attributed to a concentration-dependent biochemical activity profile.
However, 1 also bound an alternate/allosteric site that
could alternatively account for the profile. Here, we show ligand
aggregation afflicts the activity profile of 1 in biochemical
assays. However, ligand-observed fluorine (19F) and protein-observed
NMR confirms 1 binds PPARγ with two orthosteric
binding modes and to an allosteric site.