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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 [beta].sub.2 adrenergic receptor ([beta].sub.2AR) 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 [beta].sub.2AR and nucleotide-free Gs heterotrimer. The principal interactions between the [beta].sub.2AR and Gs involve the amino- and carboxy-terminal [alpha]-helices of Gs, with conformational changes propagating to the nucleotide-binding pocket. The largest conformational changes in the [beta].sub.2AR include a 14 Å outward movement at the cytoplasmic end of transmembrane segment 6 (TM6) and an [alpha]-helical extension of the cytoplasmic end of TM5. The most surprising observation is a major displacement of the [alpha]-helical domain of G[alpha]s relative to the Ras-like GTPase domain. This crystal structure represents the first high-resolution view of transmembrane signalling by a GPCR. X-ray structure of a GPCR complex G-protein-coupled receptors (GPCRs) mediate the majority of a cell's responses to hormones and neurotransmitters, and to the senses of sight, olfaction and taste. This makes GPCRs potentially the most important group of drug targets in the human body. GPCRs are deeply embedded in the cell membrane, crossing it seven times, so structure determination for these complexes is particularly challenging -- as recounted in a recent News Feature (see http://go.nature.com/ftqnx4). The eagerly-awaited X-ray crystal structure of a GPCR transmembrane signalling complex has now been determined by Brian Kobilka's group. The structure presented is of an agonist-occupied monomer of the [beta].sub.2 adrenergic receptor in complex with G.sub.s, the stimulatory G protein for adenylyl cyclase. An accompanying paper reports the use of peptide amide hydrogen-deuterium exchange mass spectrometry to probe the protein dynamics of this signalling complex., Author(s): Søren G. F. Rasmussen [sup.1] [sup.2] , Brian T. DeVree [sup.3] , Yaozhong Zou [sup.1] , Andrew C. Kruse [sup.1] , Ka Young Chung [sup.1] , Tong Sun Kobilka [...]

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 [β.sub.2] adrenergic receptor ([β.sub.2]AR) 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 [β.sub.2]AR and nucleotide-free Gs heterotrimer. The principal interactions between the [β.sub.2]AR 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 [β.sub.2]AR 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., Introduction The [β.sub.2] adrenergic receptor ([β.sub.2]AR) has been a model system for the large and diverse family of G protein-coupled receptors (GPCRs) for over 40 years. It was one of [...]

G-protein-coupled receptors (GPCRs) are seven-transmembrane proteins that mediate most cellular responses to hormones and neurotransmitters. They are the largest group of therapeutic targets for a broad spectrum of diseases. Recent crystal structures of GPCRs (1-5) have revealed structural conservation extending from the orthosteric ligand-binding site in the transmembrane core to the cytoplasmic G-protein-coupling domains. In contrast, the extracellular surface (ECS) of GPCRs is remarkably diverse and is therefore an ideal target for the discovery of subtype-selective drugs. However, little is known about the functional role of the ECS in receptor activation, or about conformational coupling of this surface to the native ligand-binding pocket. Here we use NMR spectroscopy to investigate ligand-specific conformational changes around a central structural feature in the ECS of the [β.sub.2] adrenergic receptor: a salt bridge linking extracellular loops 2 and 3. Small-molecule drugs that bind within the transmembrane core and exhibit different efficacies towards G-protein activation (agonist, neutral antagonist and inverse agonist) also stabilize distinct conformations of the ECS. We thereby demonstrate conformational coupling between the ECS and the orthosteric binding site, showing that drugs targeting this diverse surface could function as allosteric modulators with high subtype selectivity. Moreover, these studies provide a new insight into the dynamic behaviour of GPCRs not addressable by static, inactive-state crystal structures., In the ligand-free basal state, GPCRs exist in an equilibrium of conformations (6). Ligand binding modulates receptor function by stabilizing different intramolecular interactions and establishing a new conformational equilibrium. Activating [...]

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 ?2 adrenergic receptor (?2AR) 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 ?2AR and nucleotide-free Gs heterotrimer. The principal interactions between the ?2AR and Gs involve the amino- and carboxy-terminal ?-helices of Gs, with conformational changes propagating to the nucleotide-binding pocket. The largest conformational changes in the ?2AR include a 14?Å outward movement at the cytoplasmic end of transmembrane segment 6 (TM6) and an ?-helical extension of the cytoplasmic end of TM5. The most surprising observation is a major displacement of the ?-helical domain of G?s relative to the Ras-like GTPase domain. This crystal structure represents the first high-resolution view of transmembrane signalling by a GPCR. [ABSTRACT FROM AUTHOR]