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Relaxin family peptide receptor 4 (RXFP4) regulates pleiotropic biological processes. Here, authors report cryo-EM structures revealing the ligand-binding modes and key determinants of peptidomimetic agonism and subtype selectivity

A newly discovered negative allosteric modulator of the µ-opioid receptor works together with naloxone to potently block opioid agonist signalling with reduced adverse effects.

Endothelin receptors (ETAR and ETBR) are critical for vasoregulation and are targets for cardiovascular diseases treatment. Here, the authors offer a structural basis for peptide recognition selectivity and activation of both endothelin receptors.

GPR84 is an important GPCR regulating macrophage function. Here, the authors show the pro-phagocytic function of the GPR84-Gi signaling axis in native macrophages and determine a cryo-EM structure of the GPR84-Gi complex with a synthetic agonist.

Thyroid-stimulating hormone and autoantibody M22 push the extracellular domain of the thyrotropin receptor into an upright active conformation, revealing a universal activation mechanism of glycoprotein hormone receptors and providing the molecular basis of Graves’ disease, hypothyroidism and Hashimoto’s disease.

The cryo-EM structures of MRGPRX1–Gq complexes are reported, which revealed the activation and allosteric modulation mechanism of human MRGPRX1 receptor, which may enable the structure-based identification of novel analgesics.

Cryo-EM has facilitated structural studies of membrane proteins, but inactive GPCRs have remained inaccessible due to their small size. Robertson et al. demonstrate a common nanobody-based approach to streamline the determination of such structures.

In this work, the authors report Cryo-EM structures of the signaling complexes of human GPR21, an orphan GPCR and a potential metabolic disease target, and reveal unique receptor activation conformation when bound to downstream signaling proteins in the absence of any ligand.

Follicle stimulating hormone (FSH) is a glycoprotein hormone the functions of which are mediated by a G protein-coupled receptor, FSHR. Here, Duan et al. report cryo-EM structures of FSHR in active and inactive states, suggesting the molecular basis of FSH and small allosteric agonist-mediated FSHR activation.

Hydroxyl-carboxylic acid receptor 2 (HCA2) functions as a high-affinity receptor for nicotinic acid (vitamin B3). Here, authors report the cryo-EM structure of the HCA2-G_i complex with the agonist MK-6892 and inactive state crystal structures of mutation stabilized HCA2, to describe the mechanism of HCA2 signaling.

TAAR1 has a rigid consensus binding motif that binds to endogenous trace amine stimuli as well as two extended binding pockets that accommodate diverse chemotypes.

Cryo-electron microscopy structures of GPR56 and latrophilin 3 show how the released tethered agonist peptide interacts with the transmembrane domain, suggesting a model for the activation mechanism of adhesion G-protein-coupled receptors.

Cryo-EM structures of human type 1 and type 2 bradykinin receptors (B1R and B2R) reveal the basis for discrimination between the endogenous peptides des-Arg¹⁰-kallidin and bradykinin and their activation mechanism.

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 the luteinizing hormone–choriogonadotropin receptor (LHCGR), in complex with G_s and in various states of activation, reveal a distinct mechanism of receptor activation, with implications for drug discovery.

Cryo-EM structures of sulfated cholecystokinin 8 bound to the cholecystokinin A receptor in complex with G_s, G_i and G_q heterotrimers reveal structural determinants for G-protein coupling selectivity.

The human neuropeptide Y receptor Y₂ (Y₂R) is a drug target for the treatment of obesity and anxiety. Crystal structure of Y₂R bound to a selective antagonist and accompanying mutagenesis provide insights into ligand recognition and subtype specificity of NPY receptors.

The formyl peptide receptor 2 (FPR2) is involved in the pathogenesis of Alzheimer’s disease. Structures of FPR2 bound to Aβ₄₂, humanin, or formyl peptides offer insight into Aβ₄₂ neurotoxicity, humanin neuroprotection, and FPR ligand selectivity

Structures of human cholecystokinin receptors in complex with various ligands or G-proteins reveal how different ligand types are recognized and the basis of peptide selectivity in this receptor family, and suggest a stepwise activation mechanism.

Cryo-electron microscopy structures of homo- and heterodimers of mGlu2 and mGlu7 provide insights into their dimerization modes and the subunit conformational changes that characterize the activation of these class C G-protein-coupled receptors.

The authors report the structural characterization of M4R selective allosteric agonist, compound-110, as well as agonist iperoxo and positive allosteric modulator LY2119620. The cryo-EM structures of compound-110, iperoxo or iperoxo-LY2119620 bound M4R-Gi complex reveal different interaction modes and activation mechanisms of M4R. An antipsychotic activity of compound-110 with low extrapyramidal side effects in a schizophrenia-mimic mouse model is also reported. Thus, the study provides structural insights for selectively targeting mAChRs subtypes.

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.

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.

Time-resolved cryo-EM is used to capture structural transitions during G-protein activation stimulated by a G-protein-coupled receptor.

Cryo-electron microscopy structures of mGlu2 and mGlu4 bound to heterotrimeric G_i protein shed light on the molecular basis of asymmetric signal transduction by metabotropic glutamate receptors.

Cryo-electron microscopy structures of human neurotensin receptor 1 in complex with G_i1 protein and the agonist JMV449 reveal a non-canonical state that may represent an intermediate form in G-protein activation.

In the paper, Dr. Wang et al reported a cryo-EM structure of the human leukotriene B4 receptor 1 (BLT1) in complex with its native ligand leukotriene B4 (LTB4) in an active conformation complexed with Gi protein. The structure reveals the molecule determinant of LTB4 binding and the mechanism of receptor activation. These structural information will boost the understanding of LTB4-BLT1 signaling and provide a rational basis for designing novel anti-leukotriene drugs.

Humoral immunity is necessary for controlling viral infection. Ballesteros-Tato and colleagues show that development of follicular regulatory T cells is prevented by high concentrations of interleukin 2 at the peak of viral infection, but resumes at later time points to suppress autoantibody production.

Active-state structures of the κ-opioid receptor in complexes with the G-protein heterotrimers G_i1, G_oA, G_z and G_g provide insights into the actions of hallucinogenic opioids and G-protein-coupling specificity at the κ-opioid receptor.

Crystal structures of PAFR in complex with the antagonist SR 27417 and the inverse agonist ABT-491, together with accompanying experiments, provide insight into recognition of PAF and reveal an unusual ligand-dependent conformation of helical bundle.

Formyl peptide receptors (FPRs) are GPCRs that play important roles in transducing chemotactic signals in phagocytes and mediating host-defense and inflammatory responses. Here the authors present the 2.8 Å crystal structure of human FPR2 in complex with the peptide agonist WKYMVm and in combination with molecular docking, ligand-binding and signalling assays provide further insights into the binding modes of FPR2 to both non-formyl and formyl peptides.

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

Structures of the human thromboxane A₂ receptor, a member of the prostanoid family of G-protein-coupled receptors, in complex with two synthetic antagonists reveal that ligands access the ligand-binding pocket from the plane of the lipid bilayer.

Structures of the G_i-coupled CXC chemokine receptor 2 (CXCR2) in complex with CXCL8 and in complex with an allosteric antagonist provide insight into the ligand binding and activation of CXCR2 and its mode of G-protein coupling.

Direct information on the dynamic interplay between membrane proteins and lipids is scarce. Here the authors report a detailed description of these close relationships by combining lipid nanodiscs and high-pressure NMR. They report the link between pressure and lipid compositions to the conformational landscape of the β-barrel OmpX and the α-helical BLT2 G Protein-Coupled Receptor in nanodiscs.

The crystal structure of the full-length human glucagon receptor reveals the essential role of the 12-residue ‘stalk’ segment and an extracellular loop in the regulation of ligand binding and receptor activation.

Adhesion GPCRs involved in cell and matrix interactions signal through a distinct self-cleavage, self-activation mechanism.

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.

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.

Determination of the cryo-EM structures of active neurokinin-1 receptor bound to substance P or the G_q biased peptide SP6–11 reveals that interactions with the receptor extracellular loops regulate G protein signaling 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.

By solving the complex structures of third-generation antipsychotic drugs (TGAs) with the 5HT_2A receptor, Chen et al. unravel their unique pharmacology and design a novel TGA lead that has cognition-improving and potential antidepressant properties.

RXFP3 and RXFP4 regulate pleiotropic processes. Chen et al. report the cryo-EM structures of the RXFP3–Gi (bound to relaxin-3 or compound 4) and the relaxin-3–RXFP4–Gi complexes, revealing the mechanism of ligand recognition and subtype selectivity.

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.

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.

Cryo-electron microscopy structures of the adhesion G protein-coupled receptors ADGRD1 and ADGRF1 provide insight into how these receptors are activated in an intrinsic manner through a ‘stalk’ region that acts as a tethered agonist.

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.

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 FDA approved drug aprepitant is an antagonist of the Neurokinin 1 receptor (NK1R). Here the authors present aprepitant bound NK1R crystal structures and use NMR spectroscopy to gain further insights into the dynamics of aprepitant binding, which is of interest for further drug development.

A photoswitchable analog of spingosine-1-phosphate (S1P) that allows for modulation of the action of this bioactive lipid exhibits prolonged metabolic stability compared to S1P, activates S1P receptors in cells and mediates nociception in mice.