Structural insights into the dynamic process of β2-adrenergic receptor signaling

By A. Manglik, Tae Hun Kim, M. Masureel, C. Altenbach, Zhongyu Yang, D. Hilger, M. Lerch, T. S. Kobilka, Foon Sun Thian, Wayne L. Hubbell and 2 more. Cell, 2015

640 citations recorded by the source corpus.

SUMMARY 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 19F-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 towards 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.

Subfields: Cellular and Molecular Neuroscience, Computational Theory and Mathematics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/eaa937a09a4293b9c2deada46ff1fcf004ae7dcb

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cellular and Molecular Neuroscience

1. Brian K. Kobilka
2. William I. Weis
3. Bryan L. Roth

In Computational Theory and Mathematics

1. Bryan L. Roth
2. William I. Weis
3. Brian K. Kobilka

In Molecular Biology

1. Brian K. Kobilka
2. Bryan L. Roth
3. William I. Weis
4. Vsevolod Katritch
5. Raymond C. Stevens

Citations in the corpus

• DREADDs for Neuroscientists (2016, background): “The evidence for multiple GPCR states is supported by classical molecular pharmacological (Samama et al., 1993, 1994), biophysical (Gether et al., 1995), and structural studies (Manglik et al., 2015).”
• Structural insights into differences in G protein activation by family A and family B GPCRs (2020, background): “This is in contrast to the b2AR, where agonist binding alone promotes some outward movement of TM6 (38).”
• Ultrafast neuronal imaging of dopamine dynamics with designed genetically encoded sensors (2018, neutral): “1B), for which both active and inactive structure are available (20).”
• The Molecular Basis of G Protein–Coupled Receptor Activation (2018, background): “labels at positions N148C and L266C (located respectively at the cytoplasmic ends of TM4 and TM6; Figure 2) in the presence of the strong inverse agonist carazolol revealed a bimodal distance distribution that corresponds approximately to the distances expected for the bent and straight TM6 conforma”