The dynamic process of β2-adrenergic receptor activation

By R. Nygaard, Y. Zou, Ron O. Dror, Thomas J. Mildorf, Daniel H Arlow, A. Manglik, Albert C. Pan, Corey W. Liu, J. Fung, M. Bokoch and 6 more. Cell, 2013

757 citations recorded by the source corpus.

G protein-coupled receptors (GPCRs) can modulate diverse signaling pathways, often in a ligand-specific manner. The full range of functionally relevant GPCR conformations is poorly understood. Here we use NMR spectroscopy to characterize the conformational dynamics of the transmembrane core of the β2-adrenergic receptor (β2AR), a prototypical GPCR. We labeled β2AR with 13CH3ε-methionine and obtained HSQC spectra of unliganded receptor as well as receptor bound to an inverse agonist, an agonist, and a G protein-mimetic nanobody. These studies provide evidence for conformational states not observed in crystal structures, as well as substantial conformational heterogeneity in agonist- and inverse-agonist-bound preparations. They also show that for β2AR, unlike rhodopsin, an agonist alone does not stabilize a fully active conformation, suggesting that the conformational link between the agonist-binding pocket and the G-protein-coupling surface is not rigid. The observed heterogeneity may be important for β2AR’s ability to engage multiple signaling and regulatory proteins.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/ef9a023caabf7482e9a7f81913e24f45dc986fd3

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In Cellular and Molecular Neuroscience

Bryan L. Roth

In Molecular Biology

Citations in the corpus

DREADDs for Neuroscientists (2016, background): “A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript (Sounier et al., 2015; Nygaard et al., 2013), pharmacological (Weiss et al., 2013; Fenalti et al., 2014), and structural evidence (Fenalti et al., 2014; Manglik et al., 2015; Rasmussen et al., 2011; Wacker et al.,…”
Structural insights into the dynamic process of β2-adrenergic receptor signaling (2015, neutral): “These results, together with previous NMR studies (Nygaard et al., 2013), suggest that the active conformation is not the lowest energy state for agonist-bound receptor.”
Common activation mechanism of class A GPCRs (2019, neutral): “…and Cherezov, 2009; Liu et al., 2013; Weierstall et al., 2014; Stauch and Cherezov, 2018; Zhang et al., 2015), NMR (Ye et al., 2018; Chen et al., 2019; Nygaard et al., 2013; Lamichhane et al., 2015; Isogai et al., 2016; Sounier et al., 2015; Ye et al., 2016; Shimada et al., 2019), Cryo-EM (Liang…”
Protein Modelling: What Happened to the “Protein Structure Gap”? (2013, neutral): “Modeling and simulation will play a central role in exploring these alternative conformations and describing the dynamics of the transitions (Ma et al., 2011; Nygaard et al., 2013; Weinkam et al., 2012).”
A combined activation mechanism for the glucagon receptor (2020, background): “While binding of agonists promotes preactivation, full shift of the population to the active state is dependent on interaction of G proteins or G-protein mimetics with the intracellular side of the receptor (38, 39).”
Cloud-based simulations on Google Exacycle reveal ligand-modulation of GPCR activation pathways (2013, background): “b, Example antagonist chemotypes (5–8) share a 2-hydroxypropylamino core and include a carbostyril substituted pyridazinone (5), benzhydryl amine (6) and pyridone nitriles (7, 8).”