The role of ligands on the equilibria between functional states of a G protein-coupled receptor

Tae Hun Kim, Ka Young Chung, Aashish Manglik, Alexandar L. Hansen, Ron O. Dror, Thomas J. Mildorf, David E Shaw, Brian K. Kobilka, R. Scott Prosser

Research output: Contribution to journalArticleResearchpeer-review

122 Citations (Scopus)

Abstract

G protein-coupled receptors exhibit a wide variety of signaling behaviors in response to different ligands. When a small label was incorporated on the cytosolic interface of transmembrane helix 6 (Cys-265), 19F NMR spectra of the β2 adrenergic receptor (β2AR) reconstituted in maltose/neopentyl glycol detergent micelles revealed two distinct inactive states, an activation intermediate state en route to activation, and, in the presence of a G protein mimic, a predominant active state. Analysis of the spectra as a function of temperature revealed that for all ligands, the activation intermediate is entropically favored and enthalpically disfavored. β2AR enthalpy changes toward activation are notably lower than those observed with rhodopsin, a likely consequence of basal activity and the fact that the ionic lock and other interactions stabilizing the inactive state of β2AR are weaker. Positive entropy changes toward activation likely reflect greater mobility (configurational entropy) in the cytoplasmic domain, as confirmed through an order parameter analysis. Ligands greatly influence the overall changes in enthalpy and entropy of the system and the corresponding changes in population and amplitude of motion of given states, suggesting a complex landscape of states and substates.

Original languageEnglish
Pages (from-to)9465-9474
Number of pages10
JournalJournal of the American Chemical Society
Volume135
Issue number25
DOIs
Publication statusPublished - 26 Jun 2013
Externally publishedYes

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