Membrane mimetic-dependence of GPCR energy landscapes.

Autor: Thakur N; Department of Chemistry, University of Florida, 126 Sisler Hall, Gainesville, FL 32611, USA., Ray AP; Department of Chemistry, University of Florida, 126 Sisler Hall, Gainesville, FL 32611, USA., Jin B; Department of Chemistry, University of Florida, 126 Sisler Hall, Gainesville, FL 32611, USA., Afsharian NP; Department of Chemistry, University of Florida, 126 Sisler Hall, Gainesville, FL 32611, USA., Lyman E; Department of Physics and Astronomy, University of Delaware, Newark, DE, USA., Gao ZG; Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA., Jacobson KA; Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA., Eddy MT; Department of Chemistry, University of Florida, 126 Sisler Hall, Gainesville, FL 32611, USA. Electronic address: matthew.eddy@chem.ufl.edu.
Jazyk: angličtina
Zdroj: Structure (London, England : 1993) [Structure] 2024 May 02; Vol. 32 (5), pp. 523-535.e5. Date of Electronic Publication: 2024 Feb 23.
DOI: 10.1016/j.str.2024.01.013
Abstrakt: We leveraged variable-temperature 19 F-NMR spectroscopy to compare the conformational equilibria of the human A 2A adenosine receptor (A 2A AR), a class A G protein-coupled receptor (GPCR), across a range of temperatures ranging from lower temperatures typically employed in 19 F-NMR experiments to physiological temperature. A 2A AR complexes with partial agonists and full agonists showed large increases in the population of a fully active conformation with increasing temperature. NMR data measured at physiological temperature were more in line with functional data. This was pronounced for complexes with partial agonists, where the population of active A 2A AR was nearly undetectable at lower temperature but became evident at physiological temperature. Temperature-dependent behavior of complexes with either full or partial agonists exhibited a pronounced sensitivity to the specific membrane mimetic employed. Cellular signaling experiments correlated with the temperature-dependent conformational equilibria of A 2A AR in lipid nanodiscs but not in some detergents, underscoring the importance of the membrane environment in studies of GPCR function.
Competing Interests: Declaration of interests The authors declare no competing interests.
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Databáze: MEDLINE
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