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The clinical application of T cell bispecific antibodies (TCBs) is often limited by the lack of tumour-specific antigens. In this study, the authors present a strategy to increase TCB tumour-selectivity by adding an anti-CD3 moiety that can be specifically activated by tumor specific proteases in the tumor microenvironment.

Aging drives distinct molecular changes in the brain. Here, the authors use scRNAseq and MERFISH and find that in mice, aging induces subtype-specific, regionally biased changes in striatal astrocytes, marked by transcriptional repression, inflammation, and impaired neuronal interactions.

A neutralizing nanobody specific to the prefusion conformation of herpes simplex virus glycoprotein B has cross-species activity and offers insights into virus neutralization, possible immunogens and an attractive avenue for antiviral interventions.

Prokaryotic voltage-gated sodium channels possess dynamically disordered cytoplasmic C-terminal domains. Bagnéris et al. present the structure of the Magnetococcus marinusNavMs pore and C-terminal domain and reveal its role in coupling channel inactivation and opening.

Microtubules are a ubiquitous eukaryotic cytoskeletal element typically consisting of 13 protofilaments arranged in a hollow cylinder. Using CryoEM and subvolume averaging, Ferreira and Pražák et al. show that Plasmodium does not adhere to a single microtubule structure. Instead, the cytoskeleton changes substantially to produce a unique, fit for purpose structure and organisation at each stage of its life cycle.

The proteasome is a multi-protein complex that enzymatically degrades proteins. Proteolysis occurs in a barrel-shaped 20S core particle comprising three interconnected cavities, including a pair of antechambers in which substrates are held before degradation. These authors demonstrate that substrates interact actively with the antechamber walls and that the environment in this compartment is optimized to maintain the substrates in unfolded states so as to be accessible for hydrolysis.

Botulinum neurotoxin E (BoNT/E) is a major cause of botulism and paradoxically also a drug in clinical trial. Here, the authors show that BoNT/E binding and uptake require glycosylation of its host receptor SV2 with high selectivity for SV2A and SV2B over SV2C.

Characterising ensembles and populations of disordered structures is a challenge in structural biology. Here a Bayesian model allows solution data from NMR, fluorescence, and SAXS experiments to be synthesised in order to quantify the conformational distribution of disordered protein states.

Nitrogen fixation—the direct conversion of dinitrogen into ammonia or other nitrogen-containing products—is notoriously difficult to promote under mild conditions. Now, the reactivity of a multimetallic diuranium(iii) complex recently found capable of reducing and functionalizing N₂ has been explored, replacing its nitride bridge with an oxo bridge, which resulted in a markedly different reactivity.

Sequencing methods such as icSHAPE were developed to probe RNA structures transcriptome-wide in cells. To probe intact RNA structures, the authors develop icSHAPE-MaP and apply to Dicer-bound substrates showing that distance measuring is important for Dicer cleavage of pre-miRNAs.

How Draper activates phagocytosis is not well understood. Here, the authors show that two Drosophila galectins, Hdg and Ctg, are secreted from hemocytes after dendrite injury and bridge phosphatidylserine and Draper to active phagocytosis.

ZUFSP-type enzymes cleave ubiquitin chains in a linkage-specific fashion, but members from different organisms have different specificities. Using an inter-kingdom comparison of activities and structures, the authors identify the domains responsible for this discrepancy.

Poly(carboxybetaine) lipids enhance mRNA lipid nanoparticles efficacy and reduce their immunogenicity, being promising alternatives to poly(ethylene) glycol lipids used in traditional mRNA lipid nanoparticle formulations.

Integrated phenotypic screening and activity-based protein profiling identifies small molecules that decrease the expression of oncogenic transcription factors and suppress cancer cell growth by covalently targeting the RNA-binding protein NONO.

The L protein of segmented, negative strand RNA viruses contains the RNA-dependent RNA polymerase essential for virus amplification. Here, the authors report cryoEM structures of the Lassa virus L protein in active, RNA-bound states, and provide mechanistic insights.

The TAK1 kinase binds K63-linked ubiquitin specifically via its TAB2 subunit. The structure of the TAB2 NZF domain in complex with K63-linked ubiquitins now indicates that this domain interacts with neighboring ubiquitins through distinct sites, explaining the basis of specific recognition.

Here, the authors present cryoEM structures of AftB, a key mycobacterial enzyme that adds terminal arabinose residues to the cell wall. In concert with functional assays and MD simulations, mechanistic insights are presented.

Enzyme reactions at interfaces are common in both Nature and industrial applications but no general kinetic framework exists for interfacial enzymes. Here, the authors kinetically characterize 83 cellulases and identify a scaling relationship between ligand binding strength and maximal turnover, a so-called linear free energy relationship, which may help rationalize cellulolytic mechanisms and guide the selection of technical enzymes.

In bacteria Zn2+-dependent deacylases are underexplored. Here, the authors identify bacterial deacylases, providing systemic structure-function analyses to reveal the basis of substrate specificity, acyl-chain preference and inhibition.

A quantitative sensor of spatial and temporal dynamics of activity of the protein tyrosine kinase Src shows that its activity peaks 1–2 μm from the leading edge of cells undergoing lamellipodial membrane extension, and the activation is correlated with protrusion velocity.

Promoterless recombinant adeno-associated virus is used without nucleases to target the human coagulation factor IX gene to the liver-expressed albumin locus in haemophilia B mice, with an on-target integration into ∼0.5% of the albumin alleles in hepatocytes; stable F9 plasma levels at 7–20% of normal were obtained, leading to normal coagulation times in treated factor-IX-deficient mice.

Here the structure of the membrane protein complex sodium-translocating NADH:quinone oxidoreductase (Na⁺-NQR) is described; as Na⁺-NQR is a component of the respiratory chain of various bacteria, including pathogenic ones, this structure may serve as the basis for the development of new antibiotics.

The early stages of viral fusogen conformational change required for enveloped viruses to infect cells is unclear. Here, authors capture the herpesvirus fusogen, glycoprotein B, in early transitional states by cryo-EM.

X-ray and cryo-electron microscopy structures of fungal mitochondrial calcium uniporter proteins reveal a tetrameric architecture and shed light on the function of the channel.

Chronic Hepatitis B virus (HBV) is associated with elevated levels of hepatitis B surface antigen (HBsAg). Here the authors characterize the T cell responses to three variants of an HBsAg, Evn371-379, to find only the most stable L6I variant eliciting HBsAg responses, while T cells specific for L6I are detectable in both control and people with chronic HBV.

During eukaryotic ribosome biogenesis, the nascent 60S subunit is activated by SBDS and GTPase EFL1. Cryo-EM and mutational analyses reveal how SBDS–EFL1 evicts antiassociation factor eIF6 from 60S and explain the effects of disease-related SBDS mutations.

Phosphorylation of eIF4E binding proteins (4E-BPs) controls their folding and regulates cap-dependent translation. Here, the authors show that phosphorylation of the C-terminal disordered region stabilizes the non-cooperatively folded 4E-BP domain to an eIF4E binding-incompatible state to control translation.

The authors employ cryo-ET to study the structure of the palisade layer of the mature vaccinia virus core in isolation, as well as inside infected cells, revealing that it is composed of A10 protein trimers.

Genomic analysis of Plasmodium DNA from 36 ancient individuals provides insight into the global distribution and spread of malaria-causing species during around 5,500 years of human history.

The SUMO E3 ligase ZNF451 is a representative member of a new class of SUMO enzymes that execute catalysis via tandem SUMO-interaction motifs, thus allowing efficient SUMO-chain formation.

In the I-SPY2.2 trial, patients with high-risk stage 2/3 breast cancer received neoadjuvant datopotamab–deruxtecan, followed by sequential chemotherapy with or without targeted therapy, with the option of early surgical resection after each block of therapy. In a subgroup of patients, the sequential treatment strategy was superior to standard of care.

In the I-SPY2.2 trial, patients with high-risk stage 2/3 breast cancer received neoadjuvant datopotamab–deruxtecan plus durvalumab, followed by sequential chemotherapy with or without targeted therapy, with the option of early surgical resection after each block of therapy, showing that de-escalation of therapy is possible for several patient subgroups without compromising outcome and avoiding toxicity of standard chemotherapy.

Bacterial MutS2, a paralogue of the DNA mismatch-repair protein MutS, is found to bind collided ribosomes and function in translational quality control.

During HCMV infection, mitochondrial progenies derived from peripheral fragmentation can be protected from mitophagy and result in elevated respiration through a mechanism leveraging ER-mitochondria and inter-mitochondria membrane contacts.

X-ray crystal structures of the full-length TcdB exotoxin of bacterial pathogen Clostridium difficile reveal pH-dependent conformational changes that allow translocation of the toxin from endosomes into the cytosol.

BoNT/A1 invades motoneurons by binding to the neuronal receptor SV2. A combination of structural, biophysical and cellular analyses reveal that BoNT/A1 binding and uptake require glycosylation of SV2.

The X-ray crystal structure is presented of a seven-transmembrane eukaryotic SWEET glucose transporter, revealing the link between seven-transmembrane eukaryotic SWEETs and their three-transmembrane bacterial homologues and providing insight into eukaryotic sugar transport mechanisms.

Orange CaMBI, a genetically encoded bioluminescent calcium indicator consisting of calcium-sensing domain CaM, luciferase, and fluorescent proteins, reports calcium dynamics in single cells and reveals calcium oscillations in whole mouse organs.

In vivo imaging is facilitated by a bright, cyan-excitable orange fluorescent protein that is the basis of an improved bioluminescent protein.

The authors describe the VTD-deubiquitinases, a new eukaryotic enzyme family that is distantly related to herpesviral large tegument proteins. Structures of two family members with different linkage preferences allow insights into the mechanism and chain-specificity of this unusual deubiquitinase class.

Tumour expression profiling is currently used for prognostic and predictive purposes without taking into account the intra patient heterogeneity. Here the authors show that cancer cell specific signatures overcome the tumour heterogeneity effect and result in better classification of colorectal cancer patients.

S-palmitoylation regulation has been studied mostly in the cytosol and its role in mitochondria is unclear. Here the authors develop fluorescent mitochondria-targeted probes and find that depalmitoylation occurs in mitochondria and it’s influenced by alterations in mitochondrial lipid homeostasis.