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Biomacromolecules are delivered into cells using nanoparticles made of elastin and endosomal escape sequences.

Non-ribosomal peptide synthases are multimodular enzymes comprised of adenylation (A), condensation (C) and thiolation domains. Here, the authors show that non-ribosomal peptides can be generated solely by A domain substitutions, providing evidence that the postulated substrate specifying role of C-domains may be rare in nature.

Targeted protein degradation has so far been rarely applied as an antiviral strategy. Here, the authors report that macrocycle-based PROTACs targeting host protein cyclophilin A, exploited during viral infection, show potent and isoform-selective degradation resulting in antiviral activity against HIV-1 and HCV.

Analyses of the proteomes of astrocytes and neurons in a cell-specific and subcompartment-specific manner reveal distinct roles for these cell types that are relevant to obsessive–compulsive disorder and perhaps other brain disorders.

Monoclonal antibodies and ligands targeting CD40 exhibit diverse agonistic and antitumor activities that are influenced by their design. Here, the authors identify mechanistic differences between clinically relevant anti-CD40 subclasses and CD40L, focusing on the dynamics and strengths of multi-bond formation at the single-molecule level.

The human ether-a-go-go–related gene (hERG) channel regulates the heartbeat rhythm. The transition from the open to the inactivated state of human K⁺ channel ERG is analyzed by phi-value analysis, revealing a complex rearrangement of all domains (extracellular, transmembrane and cytoplasmic). The work thus reveals the sequence of conformational changes underlying selectivity filter gating, and may be relevant for other K⁺ channels.

Na+ /H+ exchangers regulate intracellular pH, sodium levels, and cell volume. Cryo-EM structures reveal lipid coordination at the dimer interfaces of NhaA with cardiolipin and endosomal NHE9 with PI(3,5)P2. These findings demonstrate how specific lipids can regulate ion-exchange activity by stabilizing dimerization with physiological ramifications.

Improving the safety and efficacy of chemotherapeutics will help to enhance their effects. Here, the authors show that intraperitoneal delivery of nanoparticle conjugates of a potent toxin prolongs tumor inhibition and survival as compared to cisplatin in advanced-stage and platinum-resistant ovarian cancer mouse models.

Continuously evolved double-stranded DNA deaminases increase the efficiency and targeting scope of all-protein base editors.

Applying an in vivo bacterial-based system for monitoring the influence of small molecules on the aggregation of model amyloid proteins expressed in the periplasm identified dopamine as a new inhibitor of hIAPP aggregation, a protein involved in type 2 diabetes mellitus.

Cytosine modifications within genomic DNA can serve as important epigenetic markers, but sequencing them at single-base resolution requires chemical modification-selective C-to-T code conversion with potential complex analysis. Now an unnatural base pair enables the sequencing of an epigenetic modification—5-formylcytosine—at single-base resolution within a Sanger sequencing format.

Catalytically inactive DNMT3B3 is crucial in de novo CpG methylation of DNA, interacting with the nucleosome core to orient catalytically active DNMT3A2 so that it can bind to nearby linker DNA.

A new targeting modality-based transcellular labeling technology called photocatalytic cell tagging enables monitoring of cell–cell interactions when combined with multiomics single-cell sequencing.

Employing pharmacology, genetics and all-optical approaches in zebrafish, Braaker et al. find that neuronal activity influences the growth of myelin sheaths along axons by signaling through metabotropic glutamate receptor 5 on oligodendrocytes.

Here the authors describe a simple reverse genetics method that relies on overlapping cDNA fragments for generation of positive-strand viruses including SARS-CoV-2 and characterize them in vitro and in vivo.

The cryo-electron microscopy structure of the hyperpolarization-activated K⁺ channel KAT1 points to a direct-coupling mechanism between S4 movement and the reorientation of the C-linker.

Due to the limited efficacy of vaccines against SARS-CoV-2 and resistance to current therapies additional anti-viral therapeutics with pan-coronavirus activity are of high interest. Here, the authors screened 2.8 billion compounds from a DNA-encoded chemical library and identified small molecules that are non-covalent inhibitors targeting the conserved 3CL protease of SARS-CoV-2 and other coronaviruses.

Single-cell RNA profiling without involving reverse transcription or microfluidics using a target panel of hybridization probes and split-pool barcoding.

TssA is an important component of the bacterial type VI secretion system (T6SS). Here, Dix et al. integrate structural, phylogenetic and functional analysis of the TssA subunits, providing new insights into their role in T6SS assembly and function.

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.

CD47 is a transmembrane receptor involved in the regulation of various signalling pathways and a promising target for immuno-oncology therapeutics. Here, the authors present the crystal structure of full-length human CD47 and provide insights into the molecular mechanism of CD47-mediated signalling.

Cancer-associated mutations in the pseudokinase domain (JH2) of JAK2 lead to constitutive activation of its tandem kinase domain (JH1). Molecular dynamics simulations, supported by mutational analysis, provide a model for JH2-JH1 interactions that explains many of the JAK2-activating disease mutations.

Zinc finger (ZF) arrays are programmable DNA-binding proteins. Here the authors report ZF-DddA-derived cytosine base editors (DdCBEs) and optimise their architectures to improve targeting; they apply these variants in vitro and in vivo to mitochondrial base editing and show higher editing than ZF deaminases.

DNA-grafted gold nanoparticles can self-assemble into shape-changing films that are powered by DNA strand exchange reactions and have two different domains that can be independently addressed using distinct chemical signals.

In this paper, translation fidelity was assessed across aging in knock-in mice with a mistranslation reporter which determines stop codon readthrough. Age-related increases in translational errors were observed in muscle and brain, but not in liver, highlighting organ-dependent declines in translation fidelity as a possible contributor to aging.

The activity of molecular motors drives the self-organization of cytoskeleton structures, leading to large-scale active flows. Now, experiments and simulations show how a gelation process enables such long-range transport in spindles.

The authors determined high-resolution cryo-EM structures of the lentiviral intasome — the nucleoprotein complex that inserts viral DNA into a host chromosome — and show that the architecture comprising 16 integrase subunits is critical for its function.

Sm FRET studies of PARP-1 recognition of DNA lesion show that binding of F1F2 fragment results in a kinked DNA, while binding of F2 fragment alone yields an intermediate state. This dynamic equilibrium of states is influenced by inhibitors.

Mutations in the cation channel PKD2 cause human autosomal dominant polycystic kidney disease but its channel function and gating mechanism are poorly understood. Here authors study PKD2 using electrophysiology and cryo-EM, which identifies hydrophobic gates and proposes a gating mechanism for PKD2.

The A3 adenosine receptor is a promising drug target for cancer, inflammation, and glaucoma. Here, authors determine atomic structures of the human A3 receptor, identifying a previously hidden binding pocket that will aid in the development of more effective A3 receptor-targeted medicines.

KCNQ1 channels are active in heart, brain and gut. Functional loss causes epilepsy and sudden arrhythmic death. Here, authors describe a key activator drug binding site, explaining isoform and drug selectivity, and point the way for new drug design.

Nucleosome flipping mediates a proofreading and processive mechanism of histone exchange driven by the chromatin remodeller SWR1.

A new DNA ‘base editor’ can change targeted A•T base pairs to G•C, allowing disease-associated mutations to be corrected and disease-suppressing mutations to be introduced into cells.

Cytokines released after T cell activation improve the efficacy of T cell therapies in mice.

Complex RNA three-dimensional structures undergo functionally important programmed conformational changes. Here, the authors report how two structurally and functionally coupled RNA domains within a viral 3′-UTR sense the ribosome through conformational changes and respond by modulating translation.

An approach combining machine learning and combinatorial chemistry enables the creation and evaluation of ionizable lipid libraries for lipid nanoparticle formulation to effectively deliver messenger RNA to several cells and tissues.

STING agonists are often limited by low circulation time and cellular uptake. The conjugation of STING agonists with polymer nanoparticles is shown to enhance stability, circulation time and cellular uptake, increasing the immunotherapeutic activity.

Paired-end reads consisting of 5′ transcription start sites and 3′ downstream sequences from transcripts in Drosophila melanogaster reveal distinct initiation patterns at different fly promoters and show that 5′ caps originating in coding regions are added posttranscriptionally.

The authors follow the folding dynamics of a nascent protein trapped during its synthesis, showing how the ribosome and a molecular chaperone shape the pathway of protein folding.

Elemental mass spectrometry imaging of biomolecules provides detailed knowledge of their abundance and location within tissue samples. This Review highlights the analytical instrumentation and strategies used to bring this technique from a research tool to clinical studies.

Bivalent molecules comprising dual functional motifs often exhibit strong target binding, however arriving at the optimal structure is challenging. Here, the authors employ EGFR as a model system for understanding a subtle difference in the linker structure of bivalent inhibitors to enhance binding against drug-resistant EGFR mutants.

Double-shelled bacteriophage φ6 is a well-studied model system used to understand assembly of dsRNA viruses. Here the authors report a near-atomic resolution cryo-EM structure of φ6 and propose a model for the structural transitions occurring in the outer shell during genome packaging.

Quantum biological electron transfer has potential in diagnostic and therapeutic settings. Here the authors report the triggered apoptosis of cancer cells using electricical input to wirelessly induce redox interactions at bio-nanoantennae in proximity to cancer cells.

Metal–organic frameworks that undergo structural transitions in response to external stimuli are promising for gas storage, but the mechanisms of such dynamics are poorly understood. Here the authors show that the structural transformation of ZIF-7 is induced by CO₂ migration through its non-uniform porous structure.

This paper highlights the far-red chemigenetic H₂O₂ reporter oROS-HT₆₃₅, which enables detailed insights into intricate intracellular and intercellular H₂O₂ dynamics, along with their environmental interactants, through spatially resolved, multiplexed real-time H₂O₂ imaging.

Ju et al. show that during three-dimensional cell migration, compression recruits cytoplasmic linker-associated proteins to microtubules; these stabilized microtubules then coordinate nuclear positioning and contractility in confined migration.

A targeted protein stabilization platform termed deubiquitinase-targeting chimera (DUBTAC) was developed based on heterobifunctional small molecules consisting of a deubiquitinase OTUB1 recruiter linked to a protein-targeting ligand.