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Crystal structures of human CB₁ bound to two cannabinoid agonists reveal key features, including a twin toggle switch and binding pocket reduction, advancing understanding of receptor dynamics and guiding cannabinoid drug design.

Solvent-mediated interaction networks control a wide range of protein functions, but their design has been neglected owing to a lack of accurate computational tools. Now it is shown that allosteric signalling membrane proteins can be engineered through such networks, revealing a broader space of designable protein interactions and functions.

Authors in this study discover a CCKBR agonist MF-8 with β-arrestin bias. This biased agonist can reduce other CCKBR signaling pathways, including Gαs-induced cAMP and Gαq/11-induced calcium signaling, thereby inhibiting the CCKBR-LTP. This discovery provides us with new ideas for developing drugs targeting CCKBR.

G-protein-coupled receptors bind endogenous ligands at sites that are frequently highly conserved. Here, authors computationally describe alternative allosteric pockets, several of which have not been targeted by synthetic ligands before.

Mapping of the neutrophil compartment using single-cell transcriptional data from multiple physiological and patological states reveals its organizational architecture and how cell state dynamics and trajectories vary during health, inflammation and cancer.

New agonists of the serotonin 5-HT_2A receptor (5-HT_2AR) confer high brain permeability and antidepressant activity and—in contrast to classic 5-HT_2AR agonists—lack psychedelic activity.

Using cryo-electron microscopy, the authors report the structures of G-protein-coupled bile acid receptor–G_s complexes and reveal the structural basis of bile acid recognition.

The crystal structure of the human κ-opioid receptor in complex with an antagonist, JDTic, is determined, with potential importance for the design of new therapeutic agents.

The authors present structures of FFA2 bound to TUG-1375/4-CMTB or GLPG0974, revealing how the receptor selects lipid chain lengths and is allosterically regulated by synthetic ligands.

Small molecule antagonists of CCR6 are potential drugs for autoimmune disorders. Here the authors present inactive structures of CCR6 bound by different allosteric antagonists from two series simultaneously, offering multiple approaches to inhibit CCR6.

The Wnt receptor Frizzled (FZD) family is crucial for both canonical (β-catenin dependent) and non-canonical (β-catenin independent) Wnt signalling. Here, the authors present the structures of FZD3 in complex with extracellular and intracellular binding nanobodies (Nbs), elucidating extracellular and intracellular interaction surfaces of functional and potentially therapeutic significance.

The orphan GPR84 plays important roles in inflammation, fibrosis, and metabolism. Here, authors report cryo-EM structures of the receptor bound to two ligands, with insights into ligand binding and entry from the extracellular milieu.

The drug Xanomeline is progressing through clinical trials for the treatment of patients with schizophrenia. Here, the authors determine a cryo-EM structure of Xanomeline bound to its primary target revealing a dual binding mode mechanism.

The cryo-EM structure and functional analyses of oxytocin bound to its receptor reveal a Mg²⁺ coordination complex in the binding pocket and find that the identity of a single residue determines whether a vasopressin/oxytocin family receptor requires Mg²⁺ as a cofactor.

Engineering protein biosensors that respond to biomolecules by triggering cellular responses has largely relied on binding rigid molecules. Here, the authors develop a computational strategy for designing signaling complexes between conformationally dynamic proteins and peptides.

Using a make-on-demand library that contains hundreds-of-millions of molecules, structure-based docking was used to identify compounds that, after synthesis and testing, are shown to interact with AmpC β-lactamase and the D₄ dopamine receptor with high affinity.

Functional trait data could guide predictions of species responses to environmental change. Here, the authors show that winner and loser shrub species in the warming tundra biome overlap in trait space and may therefore be difficult to predict based on commonly measured traits.

The cryo-electron microscopy structure of the human adenosine A₁ receptor in complex with adenosine and heterotrimeric G_i2 protein provides molecular insights into receptor and G-protein selectivity.

X-ray crystallography and molecular dynamics simulations of the μ-opioid receptor reveal the conformational changes in the extracellular and intracellular domains of this G-protein-coupled receptor that are associated with its activation.

G-protein-coupled receptors (GPCRs) transmit signals through intracellular heterotrimeric G proteins and arrestins. Here, Szczepek et al.present the structure of a common binding interface for Gα and arrestin on rhodopsin to shed light on key interactions that mediate transduction of specific signals through a single GPCR.

A cryo-electron structure of the µ-opioid receptor in complex with the peptide agonist DAMGO and the inhibitory G protein G_i reveals structural determinants of its G protein-binding specificity.

This study reports the X-ray structure of the α_1B-adrenergic G protein-coupled receptor bound to an inverse agonist, and unveils key determinants of subtype-selective ligand binding that may help the design of aminergic drugs with fewer side-effects.

Tummino et al. dock 74 million molecules against the human cannabinoid-1 receptor to find uM ligands. Optimization led to a nM agonist conferring analgesia with reduced side effects in mice, highlighting its potential as a pain therapeutic and the promise of a structure-based approach.

G protein-coupled receptors (GPCRs) are a critical target in modern drug development across a wide range of indications. Here the authors provide a comprehensive characterization of a typical GPCR, the angiotensin II (AngII) type 1 receptor (AT1R), and provide insight into its activation mechanism that suggest avenues for the design of allosteric GPCR modulators.

The authors present 7 cryo-EM structures of hallucinogenic and non-hallucinogenic compounds across multiple chemotypes bound to the 5-HT2A receptor, shedding light onto ligand specificity and signaling bias.

Recently, a class of non-catechol Dopamine D1 receptor (D1R) selective agonists with novel scaffold and improved pharmacological properties were reported. Here, authors report the crystal structure of D1R in complex with stimulatory G protein (Gs) and a non-catechol agonist Compound 1 which explains the selectivity of this scaffold for D1R over other aminergic receptors and the mechanism of activating D1R.

Different phosphorylation patterns created by GRK2 and GRK5 on the C-terminal tail of ACKR3 lead to distinct structural arrangements and dynamics of G-protein-coupled receptor–arrestin complexes, potentially explaining diverse cellular outcomes.

The authors show the dimeric structure of human LYCHOS (lysosomal cholesterol signaling), a fusion of a transporter and a G-protein-coupled receptor-like domain. The study uncovers unique transporter and receptor features and proposes a mechanism to couple cholesterol sensing, transport and signaling.

Transferring information on the GAIN domain is hampered by low sequence conservation. Here, authors introduce a generic residue numbering scheme for GAIN domains to facilitate information integration as demonstrated on cancer data.

The apelin receptor (APJR) is a drug target for cardiovascular and metabolic health. Here, authors reveal how ligand binding, receptor dimerization, and G protein coupling cooperate to regulate APJR signaling pathway, providing insight for drug discovery.

Ligands that activate GPCRs generally do so by stabilizing a particular conformation of the transmembrane helices. Here, the authors reveal a distinct activation mechanism where a ligand instead stabilizes a particular intracellular loop conformation.

The cryo-electron microscopy structure of human rhodopsin bound to the inhibitory G_i protein-coupled receptor provides insights into ligand–receptor–G-protein interactions.

This study explores apelin receptor’s role in cardiovascular function, identifying residues critical for binding through genetic variants, AlphaFold2 modelling and base editing in cardiomyocytes. Co-crystallization with biased agonist CMF-019 shows a unique binding mode versus endogenous peptides.

The MT₁ melatonin receptor differs markedly from 5-HT receptors and shows atypical ligand entry; its structure with various ligands sheds light on receptor specificity.

Adenosine A₃ receptor (A₃AR) holds promise for treating inflammatory and cancer conditions. Here, Cai et al. present cryo-EM structures of  A₃AR bound to agonists CF101 and CF102, offering insights into its activation and ligand interaction, crucial for developing targeted therapies.

There are ∼800 human GPCRs and 16 different Gα proteins; this study revealed the molecular details of Gα activation by GPCRs and suggests that a universal activation mechanism governs Gα activation—the details of this mechanism can explain how the GPCR–Gα system diversified rapidly, while conserving the allosteric activation mechanism.

The structure of the GLP-1 receptor complexed with its ligand offers insight into the mechanism of class B G-protein-coupled receptor activation.

A cryo-electron microscopy structure of the yeast pheromone receptor Ste2, a class D G-protein-coupled receptor, in its active state reveals that Ste2 is a homodimer that couples to two G proteins.

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.

Niacin is used to treat cardiovascular disease through its activation of the GPCR HCAR2. Here, the authors present cryo-EM structures of HCAR2 bound to niacin and other drug-like small molecules, which explain the basis of HCAR2 ligand recognition.

The µ-opioid receptor is a key clinical target. Here, the authors describe nanobody NbE, a selective and high affinity antagonist, which is downsized to small cyclic peptides. The work enables unique receptor targeting based on nanobody interaction.

Cryo-EM structures of complement receptors C3aR and C5aR1 bound to their respective anaphylatoxin ligands C3a and C5a reveal insights into the conserved features and topological diversities of C3aR and C5aR1 in recognizing C3a and C5a.

α_1A-adrenergic receptor (α_1AAR) regulates smooth muscle contraction and cognitive functions. Here, authors provide structural insight into α_1AAR activation and binding modes of the orthosteric ligands and an extracellular allosteric nanobody.

GPR61 is an orphan GPCR of interest for treatment of appetite disorders, such as obesity and cachexia. Here, the authors report structures of GPR61 in its active and inactive states, including with a G protein-competitive small molecule inverse agonist.

Bitopic functionalized ligands based on fentanyl can target the sodium ion-binding site of the mu-opioid receptor and selectively modulate downstream signalling pathways, potentially leading to safer analgesics.

Structural studies on the complex containing G-protein-coupled receptor kinase 2 (GRK2), neurotensin receptor 1 (NTSR1), Gα_q and the arrestin-biased ligand SBI-553 provide insights into these interactions and a foundation for the design of arrestin-biased ligands for G-protein-coupled receptors.