Ligands selectively tune the local and global motions of neurotensin receptor 1 (NTS1)

• DOI: 10.1016/j.celrep.2023.112015
• Publication Date: 2023-01-20T21:18:51Z
• Authors: Fabian Bumbak; Miquel Pons; Asuka Inoue; Juan Carlos Paniagua; Fei Yan; Hongwei Wu; Scott A. Robson; Ross A.D. Bathgate; Daniel J. Scott; Paul R. Gooley; Joshua J. Ziarek
• Keywords: Neurotensin receptor

Nuclear magnetic resonance (NMR) studies have revealed that fast methyl sidechain dynamics can report on entropically-driven allostery. Yet, NMR applications been largely limited to the super-microsecond motional regimes of G protein-coupled receptors (GPCRs). We use 13Cε-methionine chemical shift-based global order parameters test if ligands affect a thermostabilized GPCR, neurotensin receptor 1 (NTS1). establish NTS1 solution ensemble includes substates with lifetimes several, discrete timescales. The longest-lived states reflect those captured in agonist- and inverse agonist-bound crystal structures, separated by large energy barriers. observe rapid fluctuations individual methionine residues, superimposed these long-lived states, respond collectively degree fast, correlating ligand pharmacology. This approach lends confidence interpreting spectra terms local structure dihedral angle geometry. results suggest role for sub-microsecond conformational entropy GPCR discrimination.