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

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

doi:10.1016/j.celrep.2023.112015

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

Cell Rep. 2023 Jan 31;42(1):112015. doi: 10.1016/j.celrep.2023.112015. Epub 2023 Jan 20.

Authors

Fabian Bumbak¹, Miquel Pons², Asuka Inoue³, Juan Carlos Paniagua⁴, Fei Yan⁵, Hongwei Wu⁶, Scott A Robson⁷, Ross A D Bathgate⁸, Daniel J Scott⁸, Paul R Gooley⁵, Joshua J Ziarek⁹

Affiliations

¹ Department of Molecular and Cellular Biochemistry, Indiana University, Bloomington, IN 47405, USA. Electronic address: fabian.bumbak@monash.edu.
² Department of Inorganic and Organic Chemistry, Universitat de Barcelona, 08028 Barcelona, Spain.
³ Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi 980-8578, Japan.
⁴ Department of Materials Science and Physical Chemistry & Institute of Theoretical and Computational Chemistry, Universitat de Barcelona, 08028 Barcelona, Spain.
⁵ Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, VIC 3010, Australia.
⁶ Department of Chemistry, Indiana University, Bloomington, IN 47405, USA.
⁷ Department of Molecular and Cellular Biochemistry, Indiana University, Bloomington, IN 47405, USA.
⁸ The Florey Institute of Neuroscience and Mental Health and Department of Biochemistry and Pharmacology, The University of Melbourne, Parkville, VIC 3010, Australia.
⁹ Department of Molecular and Cellular Biochemistry, Indiana University, Bloomington, IN 47405, USA. Electronic address: jjziarek@indiana.edu.

Abstract

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

Keywords: CP: Cell biology; DFT; G protein-coupled receptors; GPCRs; NMR; allosteric modulator; allostery; biased agonist; conformational entropy; conformational selection; density functional theory; dynamics; methionine; pharmacological efficacy.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Drug Inverse Agonism
Humans
Ligands
Methionine
Protein Binding
Protein Conformation
Receptors, Neurotensin* / chemistry
Receptors, Neurotensin* / metabolism

Substances

Ligands
Methionine
Receptors, Neurotensin
neurotensin type 1 receptor

Abstract

Publication types

MeSH terms

Substances

Grants and funding