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Immune checkpoint inhibitors have shown promise in tumour immunotherapy but resistance has been seen. Here using pre-treatment hepatocellular carcinoma patient biopsies from patients scheduled for immunotherapy, the authors implicate BCL9 and show that a BCL9-targeting peptide promotes anti-tumour immunity in mouse models through targeting macrophages and promoting anti-tumour T cell responses.

Mapping brain connections is critical for decoding brain functions. Here, the authors present an integrated resource of awake resting-state fMRI and neuronal tracing data of marmosets to understand structural-functional relationships of brain connections.

Structural and biochemical studies of the monkeypox virus core protease show that it exists as an active homodimer and indicate that the substrate-binding sites of core proteases are a promising target for antiviral drugs.

Miniature gene editing tools are highly desired for efficient in vivo delivery and disease treatment. Here, the authors reported engineering hypercompact TnpB-ωRNA for robust gene editing with minimal off-target effect in cultured cells and use it to rescue fatal genetic liver disease in a tyrosinaemia mouse model.

A physics-informed deep learning model, PBCNet, is proposed for predicting the relative binding affinity of ligands in order to improve guiding structure-based drug lead optimization.

Cryo-electron microscopy structures of the noradrenaline transporter in the apo state, bound to noradrenaline and bound to various antidepressants shed light on the substrate transport, molecular recognition and dimeric architecture of this protein.

Nuclear SREBP2 forms nuclear condensates through its N-terminal intrinsically disordered region, which is essential for the transcriptional activation of lipogenic genes.

The antidiabetic drug acarbose is shown to be degraded by a Klebsiella species present in the human gut, which is enriched with acarbose treatment and might mediate acarbose resistance and variations in clinical efficacy observed in patients.

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.

Prostaglandin F_2α receptor (FP) is the primary therapeutic target for glaucoma and several other diseases. Here, the authors reveal structural mechanisms of ligand recognition, receptor activation, and G protein coupling by FP.

The authors show that adriamycin induces global changes on chromatin conformation associated with phase transitions mediated through Histone H1.

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

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.

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.

The identification of post-translational modifications (N-glycosylation and phosphorylation) in GPR52, an orphan G-protein-coupled receptor, shapes the intrinsic signaling bias and can modulate GPR52-dependent accumulation of the huntingtin protein in brain cells.

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.

Phase separation of androgen receptor underlies mutation-mediated antiandrogen resistance. A phenotypic screen enabled the discovery of ET516, which disrupts androgen receptor phase separation and effectively suppresses the growth of prostate cancer.

The mechanism underlying hepatocytes apoptosis, a key process in the progression of nonalcoholic steatohepatitis, remains unclear. Here, the authors identify UGDH and its catalytic product UDP-glucuronate as suppressors of NASH-associated liver damage by inhibiting RIPK1- dependent hepatocyte apoptosis.

MRGPRX1 is a key GPCR expressed in the DRG for itch perception, generating scratch or avoidance behaviors. Here, authors provide structural and pharmacological insights into itch sensation, activation and G-protein signaling downstream of MRGPRX1.

Structures of the glucagon receptor bound to β-arrestin 1 are reported, providing further information about the arrestin-mediated modulation of G protein-coupled receptors.

The cryo-EM structures reveal orphan receptor GPR119 as the receptor for LPC. The structures with biochemical and functional data highlight evidence for LPC function in glucose regulation, and provide templates for drug design targeting GPR119.

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.

The basis for the diverse peptide-binding modes and the G protein selectivity of peptide GPCRs remains elusive. Here, the authors offer a structural basis for allosteric-like agonism and G protein selectivity of a neuropeptide GPCR, galanin receptor.

Neuromedin U receptors (NMURs) are potential drug targets for obesity and inflammatory disorders. Here, the authors report structural basis for neuromedin recognition and activation mechanism of NMURs.

Macrocyclization of bioactive acyclic molecules provides a potential avenue to yield novel chemical scaffolds with improved pharmacological properties. Here, the authors propose a deep learning based macrocyclization method to generate diverse macrocycles from a given acyclic molecule.

This study presents a novel Type I-A CRISPR-Cas3 variant for precise HPV diagnosis. It demonstrates dual activation modes and robustness without stand-alone Cas3 activity, enhancing CRISPR-Cas3 diagnostic applications.