Crystal Structure of the β2Adrenergic Receptor-Gs protein complex

By S. Rasmussen, Brian T DeVree, Y. Zou, A. Kruse, K. Chung, T. S. Kobilka, Foon Sun Thian, P. S. Chae, E. Pardon, D. Calinski and 10 more. Nature, 2011

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G protein-coupled receptors (GPCRs) are responsible for the majority of cellular responses to hormones and neurotransmitters as well as the senses of sight, olfaction and taste. The paradigm of GPCR signalling is the activation of a heterotrimeric GTP binding protein (G protein) by an agonist-occupied receptor. The β2 adrenergic receptor (β2AR) activation of Gs, the stimulatory G protein for adenylyl cyclase, has long been a model system for GPCR signalling. Here we present the crystal structure of the active state ternary complex composed of agonist-occupied monomeric β2AR and nucleotide-free Gs heterotrimer. The principal interactions between the β2AR and Gs involve the amino- and carboxy-terminal α-helices of Gs, with conformational changes propagating to the nucleotide-binding pocket. The largest conformational changes in the β2AR include a 14 Å outward movement at the cytoplasmic end of transmembrane segment 6 (TM6) and an α-helical extension of the cytoplasmic end of TM5. The most surprising observation is a major displacement of the α-helical domain of Gαs relative to the Ras-like GTPase domain. This crystal structure represents the first high-resolution view of transmembrane signalling by a GPCR.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology, Spectroscopy

View Paper: https://www.semanticscholar.org/paper/9c006b7d672f2908e32303d7b11de05b9fe3562e

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Citations in the corpus

Regulation of µ-Opioid Receptors: Desensitization, Phosphorylation, Internalization, and Tolerance (2013, background): “Pioneering studies of rhodopsin (Choe et al., 2011) and the b2-adrenergic receptor (Rasmussen et al., 2011; Rosenbaum et al., 2011) provide interesting clues.”
A glimpse of structural biology through X-ray crystallography. (2014, background): “Structure of an agonist-bound b2 adrenergic receptor in complex with a nucleotide-free Gs heterotrimer provided a preliminary answer to how ligand binding to GPCR triggers the activation of G protein in the cytoplasm (Rasmussen et al., 2011).”
GPCR Network: a large-scale collaboration on GPCR structure and function (2012, background): “A key breakthrough for the field was the structure determination of a complex of β 2 -AR with the G s protein 44 , setting the stage for studies of GPCR complexes with their intracellular partner proteins.”
The RCSB PDB “Molecule of the Month”: Inspiring a Molecular View of Biology (2015, background): “From top to bottom: DNA polymerase [16], ribosome [17,18], hemoglobin [19], ATP synthase [20,21], a G-protein bound to a G-protein-coupled receptor (GPCR) [22], and the collagen triple helix [23].”
Ultrafast neuronal imaging of dopamine dynamics with designed genetically encoded sensors (2018, background): “We selected a subset of GPCRs, including Gs-coupled β1 and β2 adrenergic receptors (B1AR and B2AR); Gicoupled k and μ-type opioid receptors (KOR, MOR), and α2 adrenergic receptor (A2AR); and Gq-coupled 5-hydroxytryptamine (serotonin) receptor-2A (5HT2A) and melatonin type-2 receptor (MT2).”
Structural Features for Functional Selectivity at Serotonin Receptors (2013, background): “For the 5-HT1B receptor, we observe that the P-I-F configuration is essentially identical to that of the active-state of β2AR (β2AR-R*, PDB ID: 3SN6, (18)) (Fig.”
DREADDs for Neuroscientists (2016, background): “…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., 2013)—is crucial for understanding how GPCR-based chemogenetic technologies can be harnessed in neuroscience.”
5-HT2C Receptor Structures Reveal the Structural Basis of GPCR Polypharmacology (2018, positive): “Compared to the active and inactive state structures of b2-adrenergic receptor (b2AR) (Rasmussen et al., 2011; Wacker et al., 2010), 5-HT2C-RIT resembles the inactive state conformation of b2AR, whereas 5-HT2C-ERG shows all ‘‘active-like features’’ exemplified by the active state of b2AR (Figure S2)”