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Zeng et al. applied single-particle cryo-electron microscopy to native samples isolated from the human parasite Toxoplasma gondii, determining multiple structures of key components of the conoid, a cone-shaped organelle essential for host cell invasion.

AAA proteases must unfold substrates before degradation. Here the authors report cryo-EM structures to visualize how these machines achieve this by pulling the substrate tightly against their narrow axial channel and encircling the substrate’s folded domain using only the unfoldase’s flexible loops.

Rashan, Bartlett and colleagues show that mammalian 4-hydroxy fatty acids are primarily catabolized by ACAD10 and ACAD11 (atypical mitochondrial and peroxisomal acyl-CoA dehydrogenases, respectively) that use phosphorylation in their reaction mechanisms.

Here, the authors present a method to rapidly isolate actively translating ribosomes in a time- and cost-effective manner using poly-lysine. The method is compatible with a wide variety of cell and tissue types and can be used for mass spectrometry, cryoEM, and in vitro translation assays.

Mediator proteins such as BRCA2 and Rad52 direct formation of Rad51 filaments in Homologous Recombination. Here, the authors present cryoEM structures of Saccharomyces cerevisiae Rad52 revealing a homodecamer and Rad51 binding to two regions in Rad52.

CryoEM snapshots of the nitrogenase-like DPOR protein complex captured during turnover reveal that asymmetric conformational changes, substrate recognition, and an interplay between copper and iron sulfur metalloclusters is required for electron transfer.

Structures of the bifunctional heme transporter cytochrome c synthase CcsBA in closed and open states show how heme binding in the periplasmic site induces a conformational shift, exposing the heme and facilitating its transfer to apocytochrome c.

δ-Opioid receptors (δOR) are promising targets for pain management with reduced side effects. Here, the authors use a structure-based approach to design and characterize C6-Quino, a selective δOR partial agonist, highlighting its potential therapeutic relevance.

Viruses generally have compact genomes, resulting in many viral mRNAs with short 5’ untranslated regions. An antiviral complex exploits this feature of viral mRNAs to selectively inhibit viral protein synthesis and repress viral replication.

Cryo-electron microscopy structures reveal the mechanisms underlying multiple-substrate specificity, coupling of epoxidation with carboxylation and allosteric motions during VKGC catalysis, offering potential strategies for targeting haemostatic and non-haemostatic disorders associated with defects in γ-carboxylation.

Metazoans have evolved endocrine systems that signal through dimerized receptors in response to cognate hormones. These authors characterize a nematode homolog of such human receptors, presenting the cryo-EM structure of an asymmetric dimer that embodies properties of the human receptors.

Streptomyces are discovered to produce antibacterial protein complexes that selectively inhibit the hyphal growth of related species, a function distinct from that of the small-molecule antibiotics they are known for.

Durable agonism of NPR1 achieved with a novel investigational monoclonal antibody could mirror the positive hemodynamic changes in blood pressure and heart failure identified in humans with lifelong exposure to NPR1 coding variants.

Despite advances in GPCR structures and peptide design, creating high-affinity ligands remains a challenge. Here the authors develop a computational method, successfully identifying peptide-based molecules for KOR: their platform shows promise for streamlined GPCR ligand discovery.

To bypass the limitations of detergents, Ren et al. developed peptide scaffolds that extract membrane proteins directly into lipid nanodiscs, preserving the native environment for structural and functional studies of previously inaccessible membrane protein complexes

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.

Live attenuated SIV vaccines protect nonhuman primates from infection with pathogenic wild-type SIV, but the crucial mechanisms have not been clear. In this issue, Louis Picker and colleagues show that protection by live attenuated vaccines against intravenous SIV challenge in rhesus macaques is associated with SIV-specific T cell response in the lymph nodes, and not the blood, and persistent SIV replication in lymph node follicular T helper cells.

Cryo-EM structures of radial spokes and nexin−dynein regulatory complex (N-DRC) attached to doublet microtubules isolated from Chlamydomonas reinhardtii provide a model for mechanoregulation of motile cilia.

This study uncovers that certain κ-opioid receptor inverse agonists form receptor–G protein complexes, even in inactive states, challenging the classic GPCR activation model.

In this Opinion article, Dan Barouch and Louis Picker discuss recent data regarding the clinical development of novel serotype adenovirus and cytomegalovirus vaccine vectors for use in HIV-1 vaccines.

Human leucocyte antigen E (HLA-E) directly engages NK cells but also presents antigen to CD8⁺ T cells. Here the authors show crystal structures of HLA-E in complex with peptides derived from HIV and Mycobacterium tuberculosis, and describe binding conformations, the positional impact of residues involved and discuss implications for functional presentation to CD8⁺ T cells.

The authors present a generalisable computational approach to stabilize class I fusion proteins in the prefusion state. The method was used to stabilize the fusion proteins of RSV, hMPV, and SARS-CoV-2 viruses, with the designs structurally validated and RSV F protein assessed in a neutralization assay.

This study reveals the mechanism by which protons gate a CLC-type Cl⁻/H⁺ exchanger. The authors show that pH-dependent concerted structural rearrangements open the H⁺ pathway, which allosterically enables the Cl⁻ pore opening and ion exchange.

Monoamines and neurotoxicants share a binding pocket in VMAT1 featuring polar sites for specificity and a wrist-and-fist shape for versatility, and monoamine enrichment in storage vesicles arises from dominant import via favoured lumenal-open transition of VMAT1 and protonation-precluded binding during its cytoplasmic-open transition.

The optical and electronic properties of cesium lead halide perovskite nanocrystals are dictated by the band-edge exciton, whose physics is not elucidated. Here, the authors unveil its fine structure and demonstrate that the ground dark singlet state promotes the creation of biexcitons at low temperatures and thus correlated photon pairs.

This Consensus Statement clarifies the existing subset-based nomenclature for T cells. Furthermore, it proposes an alternative modular nomenclature that is designed to be brief and flexible and to avoid ambiguity and unwanted implications. The authors also provide guidance on how T cell nomenclature should be described in research papers.

Influenza genetic diversity is a key challenge in the design of a universal influenza vaccine that protects against different strains of influenza virus. Here, Malouli and colleagues demonstrate use of a cytomegalovirus-based T cell vaccine that induces immunity and can protect macaques from lethal avian influenza challenge with heterologous strains of influenza and suggest protection is linked to the generation of lung-resident influenza-specific CD4⁺ T cells.

Issue:Vaccines that induce T cell responses to simian immunodeficiency virus are able to reduce virus load in infected macaques. Such vaccines typically induce central memory T cells that must expand before gaining full antiviral functions. Picker and his colleagues show that a new replicating anti-SIV vaccine, based on the persistently infecting cytomegalovirus, which preferentially induces effector memory T cells in mucosal tissues, can reduce the likelihood that the macaques become infected in the first place (pages 244–246).

The relationship between DNA damage response (DDR) and regulation of the tolerance to glucose restriction is currently unclear. Here the authors reveal that maintaining a physiological level of histones by Rad53-Spt21 is necessary for glucose tolerance via multiple parallel pathways, including derepression of subtelomeric genes and acetyl-coA regulation by histone acetylation.

Efforts to make a prophylactic HIV vaccine have identified monoclonal antibodies that potently suppress viral replication. Studies in monkeys show that these reagents effectively treat HIV infection. See Article p.224 & Letter p.277

Early and prolonged administration of antiretroviral therapy to SIV-infected and post-exposure-vaccinated rhesus macaques was associated with absence or delay of detectable virus after therapy interruption.

Pandey, Bera, Shi et al. report the cryo-electron microscopy structure of the Rous sarcoma virus octameric intasome complex stabilized by a HIV-1 integrase strand transfer inhibitor. This new structure highlights the intrinsic flexibility of the distal integrase subunits and suggests that ordered conformational transitions occur within the conserved intasome core during the assembly process.

The dual nature of non-polymorphic MHC-E as a ligand for innate receptors and as an antigen-presenting protein raises the possibility of new, universally effective vaccines and immunotherapies for infectious disease and cancer that are independent of the MHC haplotype of an individual.

Complete vaccine-mediated immune control of highly pathogenic Mycobacterium tuberculosis is possible if immune effector responses can intercept the infection at its earliest stages.