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Through the use of cryo-electron microscopy and molecular dynamics stimulations, mechanistic insight into the binding of an odorant to the human odorant receptor OR51E2 is provided.

A cryo-electron microscopy structure of β-arrestin 1 in complex with the M2 muscarinic receptor reconstituted in lipid nanodiscs is reported.

The β₁-adrenergic receptor (β₁AR) is a G-protein-coupled receptor (GPCRs) that binds catecholamine ligands. Here the authors employ site-specific labelling and ¹⁹F NMR measurements to characterise the structural changes and dynamics in the cytoplasmic region of β₁AR upon agonist stimulation and coupling to a G_s-protein-mimetic nanobody.

Comparative analysis of inactive/active-state structures reveals molecular mechanistic maps of activation of the major GPCR classes. The findings and new approaches lay the foundation for targeted receptor-function studies and drugs with desired modalities.

Cryo-EM structures of somatostatin 14- and octreotide-bound somatostatin receptor 2 reveal a flexible extracellular domain for recognizing different ligands and, together with functional assays, identify the basis of SSTR subtype selectivity.

Cryo-electron microscopy structures of heterodimeric and homodimeric full-length GABA_B receptors, combined with cellular signalling assays, shed light on the mechanisms that underpin signal transduction mediated by these receptors.

Antagonists of Smoothened, a class F GPCR involved in the hedgehog pathway, have been developed to treat some cancers. Here Wang et al.report structures of Smoothened in complex with antagonists and an agonist, and describe how mutations may result in resistance to anti-Smoothened treatment.

A chemogenomic approach to explore activity of the free fatty acid receptor FFA2 independently of the related FFA3 shows that FFA2 in differentiated adipocytes and colonic crypt cells in mice is responsible for regulated lipolysis and GLP-1 release.

Allosteric GPCR modulators can achieve exquisite subtype selectivity, but the underlying mechanism is unclear. Using molecular dynamics simulations, the authors here identify a previously undetected dynamic pocket in muscarinic GPCRs that is critical for subtype selectivity of allosteric modulators.

The authors show G protein subtype selectivity at the β₁-adrenergic receptor is driven by the binding kinetics of ternary complex formation. Bound to G protein, the receptor adopts conformations that differ from its agonist-bound solution states.

A synthetic yeast-based therapeutic that secretes an ATP-degrading enzyme in response to pro-inflammatory extracellular ATP in the gut reduces intestinal inflammation, fibrosis and dysbiosis in mouse models of colitis and enteritis.

Cryo-EM structures of complexes between GRK1 and rhodopsin shed light on how a small number of GRKs can selectively recognize and be activated by hundreds of different G-protein-coupled receptors.

The cryo-EM structure of a megacomplex between chimeric GPCR, G protein and β-arrestin in their canonical active conformations provides insight into the basis of sustained G protein signaling upon megacomplex internalization.

A crystal structure of the GPCR target of endocannabinoid signaling lipids and drugs, CB1, bound to a negative allosteric modulator (NAM) and an agonist, shows that the NAM binds to a membrane-embedded site reminiscent of the binding site of cholesterol.

Structures of GPCR neurotensin receptor 1 (NTSR1) in complex with neurotensin and Gα_i1β₁γ₁ in a lipid bilayer environment and without stabilizing antibodies reveal extensive interactions at the GPCR–G protein interface.

Cryo-EM structures of µ-opioid receptor complexes with two agonists coupled to molecular dynamics simulations and functional assays highlight distinct efficacy for G protein subtype activation and β-arrestin recruitment.

A negative allosteric modulator of the G-protein-coupled receptor β₂-adrenergic receptor binds to a membrane-facing surface adjacent to a molecular switch for receptor activation, and its binding disrupts a water-mediated polar network stabilizing an inactive switch conformation.

The membrane is an integral component of the G protein-coupled receptor signaling machinery. Here authors demonstrate that lipids regulate the signaling efficacy and selectivity of the ghrelin receptor GHSR through specific interactions and bulk effects and observe PIP2 and GM3 induced shifts of the conformational equilibrium of GHSR away from its inactive state.

STING is a promising drug target, but selective activation is necessary for safety and efficacy. Researchers have developed a two-component prodrug system for potent pharmacological activation of STING that offers excellent tumour targeting.

Human orexin receptors (hOX₁R and hOX₂R) are GPCRs involved in sleep regulation. Structures of hOX₁R bound to a selective antagonist or to a dual antagonist, functional assays and computational analyses reveal the basis for subtype selectivity.

Four crystal structures of the human serotonin receptor 5-HT_2BR in complex with chemically and pharmacologically diverse drugs elucidate the structural bases for receptor activation, agonist-mediated biased signaling and β-arrestin2 translocation.

An online and interactive G-protein coupled receptor (GPCR) structure analysis platform allows any researcher to analyze and visualize a plethora of structure–function relationships across the scales of atomic interactions to protein backbone rearrangements.

Tell Bartolo Luque and Fernando Ballesteros how far the Sun is from the Earth, and they will tell you the size of the Universe.

The X-ray crystal structure of a rat neurotensin receptor in complex with the C-terminal portion of neurotensin is presented; this is the first structure of a member of the β group of class A G-protein-coupled receptors.

A quantitative covalent labeling strategy reveals that multiple ligand-specific conformational states are present in the G protein–coupled β₂-adrenergic receptor. Their existence may underlie 'biased agonism', which describes the differential abilities of agonists to activate distinct signaling mechanisms downstream of GPCRs.

The active-state structure of a GPCR occupied by a partial agonist, β₂AR with salmeterol, together with mutagenesis and biophysical studies, explains this ligand's unusual pharmacological profile.

Recent studies revealed that G protein-coupled receptors rapidly interconvert between multiple states. Here, authors use the kappa opioid receptor (KOR) and show how two state-dependent nanobodies provide real-time reporting of ligand stabilized states with KOR and other GPCRs.

Solid-state NMR analyses reveal that the free backbone carbonyl groups associated with proline residues in the transmembrane helices play a key role in mediating rhodopsin activation.

The X-ray crystal structure of the transmembrane portion of the human glucagon receptor, a class B G-protein-coupled receptor (GPCR), is solved in the presence of the antagonist MK-0893, with potential implications for the development of therapeutics that target other class B GPCRs.

Machine learning models showed that social disparities, cardiometabolic disease and mental health were the main predictors of aging in Latin American populations, with these factors being more pronounced in low- and middle-income compared to high-income Latin American countries.

G protein–coupled receptors (GPCRs) mediate transmembrane signaling. The crystal structure of β1-adrenergic receptor in its ligand-free, basal state is now presented. The structure reveals an inactive conformation with two alternating dimer interfaces.

Rhodopsin signalling is triggered by the light-induced isomerization of its 11-cisretinal chromophore. Here, the authors use NMR spectroscopy to define retinal orientation and interactions in the active metarhodopsin II intermediate, proposing a two-stage mechanism for rhodopsin activation.

The atypical chemokine receptor 3 (ACKR3) is important for cell migration in development and cancer. Here the authors combine radiolytic footprinting, disulfide trapping, mutagenesis and molecular modelling to characterize the ligand interactions and ligand-induced conformational changes in ACKR3.

The future of marine ecosystem function under global change may be predicted by examining past trends. Here, the authors examine mass marine mortality data from 389 benthic Mediterranean species (1986–2020), highlighting heightened vulnerability within specific trait categories.

Lu and colleagues show that signaling through the lactate receptor HCAR1 in colorectal tumor cells promotes the recruitment of immunosuppressive CCR2⁺ PMN-MDSCs and that inhibition of HCAR1 by reserpine augments the CD8⁺ T cell-mediated antitumor immune response.

G protein-coupled receptors are a large family of signalling proteins that mediate cellular responses primarily via G proteins or arrestins, and they are targets of one-third of the current clinically used drugs; here, an active form of human rhodopsin bound to a pre-activated form of the mouse visual arrestin-1 is determined, revealing unique structural features that may constitute essential elements for arrestin-biased signalling.

GPR40 is a G-protein coupled receptor that binds to free fatty acids, mediating insulin and incretin secretion. Here, the authors present the crystal structure of human GPR40 with an agonist bound to an allosteric site located near the lipid-rich region that suggests a mechanism for biased agonism.

β₁-adrenergic receptors are expressed in cardiac tissue and stimulated by the sympathetic nervous system. Here, the authors use NMR spectroscopy to unravel the conformational diversity upon β₁-adrenergic receptor activation and provide structural insights into partial agonism and basal activity.

Ligand-induced biased signaling is thought to result in part from ligand-specific receptor conformations that cause the engagement of distinct effectors. Here the authors trace and evaluate the impact of mutations of the β2–adrenergic receptor on multiple signaling outputs to provide structural-level insight into the determinants of GPCR functional selectivity.

Aberrant expression and activity of G proteins and G-protein-coupled receptors (GPCRs) are frequently associated with tumorigenesis. Recent deep sequencing studies have shown that nearly 20% of human tumours harbour mutations in GPCRs. This Analysis article reviews these findings and the indications that G proteins, GPCRs and their signalling pathways represent novel therapeutic targets for cancer prevention and treatment.

A virtual screen of the GPCR D3R based on a homology model prior to publication of the crystal structure and a subsequent virtual screen based on the crystal structure of the receptor once it became available both identified new ligands with verified activities.

Correlations between tree species diversity and tree abundance are well established, but the direction of the relationship is unresolved. Here the authors use path models to estimate plausible causal pathways in the diversity-abundance relationship across 23 global forests regions, finding a lack of general support for a positive diversity-abundance relationship, which is prevalent in the most productive lands on Earth only

Meteorology measurements from NASA’s Perseverance rover on Mars reveal a diversity of processes at work in the atmospheric boundary layer at Jezero crater over a range of temporal scales.

Many G protein-coupled receptors (GPCRs) have endogenous peptide agonists, and modifying the sequence of these peptides has led to some successful therapeutics. In this Review, Davenport and colleagues discuss strategies to generate effective GPCR-targeted peptide therapeutics by introducing chemical novelty, extending plasma half-life, improving a therapeutic’s drug-like properties or generating biased ligands. These approaches could overcome some of the challenges in developing peptide therapeutics.

Reversible mitochondrial stress leading to improved mitochondrial function (mitohormesis) has been reported as an anti-aging mechanism. Here the authors report that harmol (a beta-carboline compound) induces mitohormesis in peripheral organs, alleviates aging-related phenotypes in mice, and extends lifespan in invertebrate models.

The authors analyse tree responses to an extreme heat and drought event across South America to understand long-term climate resistance. While no more sensitive to this than previous lesser events, forests in drier climates showed the greatest impacts and thus vulnerability to climate extremes.

Structural and functional studies show that the MT₂ melatonin receptor, unlike the MT₁ receptor, contains an extracellular opening for ligand entry, shedding light on receptor subtype specificity.

Crystal structures of the neuropeptide Y₁ receptor in complex with two distinct antagonists combined with NMR, molecular docking and mutagenesis studies inform a proposed model for receptor–agonist binding.