Structural Insights into the Dynamic Process of β2-Adrenergic Receptor Signaling. Cell 2015 May 21;161(5):1101-1111
Date
05/20/2015Pubmed ID
25981665Pubmed Central ID
PMC4441853DOI
10.1016/j.cell.2015.04.043Scopus ID
2-s2.0-84930226866 (requires institutional sign-in at Scopus site) 491 CitationsAbstract
G-protein-coupled receptors (GPCRs) transduce signals from the extracellular environment to intracellular proteins. To gain structural insight into the regulation of receptor cytoplasmic conformations by extracellular ligands during signaling, we examine the structural dynamics of the cytoplasmic domain of the β2-adrenergic receptor (β2AR) using (19)F-fluorine NMR and double electron-electron resonance spectroscopy. These studies show that unliganded and inverse-agonist-bound β2AR exists predominantly in two inactive conformations that exchange within hundreds of microseconds. Although agonists shift the equilibrium toward a conformation capable of engaging cytoplasmic G proteins, they do so incompletely, resulting in increased conformational heterogeneity and the coexistence of inactive, intermediate, and active states. Complete transition to the active conformation requires subsequent interaction with a G protein or an intracellular G protein mimetic. These studies demonstrate a loose allosteric coupling of the agonist-binding site and G-protein-coupling interface that may generally be responsible for the complex signaling behavior observed for many GPCRs.
Author List
Manglik A, Kim TH, Masureel M, Altenbach C, Yang Z, Hilger D, Lerch MT, Kobilka TS, Thian FS, Hubbell WL, Prosser RS, Kobilka BKAuthor
Michael Lerch PhD Assistant Professor in the Biophysics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Adrenergic beta-AgonistsAmino Acid Sequence
Benzoxazines
Humans
Isoproterenol
Magnetic Resonance Spectroscopy
Models, Molecular
Molecular Sequence Data
Nuclear Magnetic Resonance, Biomolecular
Receptors, Adrenergic, beta-2
Signal Transduction
