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Interactions between the endoplasmic reticulum membrane protein complex (EMC) and the high-voltage-activated calcium channel Ca_Vα₂δ are mutually exclusive, and EMC-to-Ca_Vα₂δ hand-off involves a divalent ion-dependent step and Ca_V1.2 element ordering.

RSV and hMPV infections pose significant health risks in vulnerable populations. Here, the authors used a systematic approach to identify mutations critical for fusion protein metastability and rationally design uncleaved prefusion-closed trimers for RSV and hMPV F proteins that induce robust antibody responses in vivo.

Unbiased chemical biology strategies for direct readout of small molecule protein interactomes provide advantages over target-focused approaches. Here, the authors describe the BioTAC system, a network-scale small molecule guided proximity labeling platform, to rapidly identify ligand-target interactomes.

The auxiliary subunit Cavβ regulates calcium channel density in the plasma membrane, but the mechanism by which this occurs has been poorly defined. Altier et al. find that Cavβ prevents ubiquitination of the Cav1.2 channels by the RFP2 ubiquitin ligase and subsequent targeting of the channels for proteasomal degradation.

DNA polymerase θ is a polymerase-helicase essential for microhomology-mediated end-joining (MMEJ) or alternative end-joining of DNA. Here the authors use biochemical and biophysical methods to reveal how full-length human DNA polymerase θ performs MMEJ at the molecular level.

Fifty years ago, Köhler and Milstein introduced the world to hybridoma technology for the generation of monoclonal antibodies. Scientists have subsequently built upon this seminal discovery to develop antibody-based therapies for numerous diseases, with millions of patients benefiting from such drugs. To mark 50 years of monoclonal antibodies, this Review from Chan, Martyn and Carter provides an overview of how antibody engineering strategies have continued to improve antibody-based therapeutics, chiefly focusing on antibody-mediated targeting of B cells and also human epidermal growth factor receptor 2 (HER2)⁺ cancers. The authors also highlight the promise of emerging tools, including artificial intelligence, for development of the next generation of antibody-based therapeutics.

Existing click chemistry-mediated approaches for dynamic imaging can suffer from low detection sensitivity. Here, the authors report a nitrile-aminothiol bioorthogonal fluorogenic probe with a ‘cleavage-click-assembly’ sensing action for ultrasensitive detection of small cancerous lesions.

Combined single-molecule spectroscopy, hydrogen–deuterium exchange and molecular dynamics approaches reveal that agonist activation of metabotropic glutamate receptors entails population of several intermediary states before G protein coupling.

A new acid-degradable linker termed ‘azido-acetal’ has been developed that rapidly hydrolyses at pH 6.0 but is stable at pH 7.4. Lipid nanoparticles made with this linker delivered mRNA in vivo and in vitro better than traditional lipid nanoparticles.

Induced proximity by molecular glues is a strategy that leverages the recruitment of proteins to facilitate their modification or degradation. Here the authors present unbiased quantitative proteomic, biochemical and computational workflows that uncover hundreds of CRBN molecular glue targets using recombinant protein and cell lysate.

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.

Protocol for fabricating synthetic viscoelastic antigen-presenting cells and their application in T cell engineering. These synthetic cells support robust T cell activation and expansion and improve chimeric antigen receptor transduction efficiency.

Genetically encoded voltage sensors are useful tools for the analysis of membrane potential and its influence on cell function. Here, the authors present a range of these sensors with varying colours for rapid and sensitive neuronal voltage imaging.

High-density multimodal soft bioelectronic fibres provide a platform for minimally invasive implantable electronics, where diverse sensing and stimulation functionalities can be effectively integrated.

CRISPR base editors are limited by protospacer adjacent motif (PAM) sequences and specific editing windows. Here, authors developed ABE-Ultramax, a suite of adenine base editors with high efficiency, low indel rates, and flexible PAM requirements, enabling precise biallelic editing in zebrafish.

Kucharska, Ivanochko and Hailemariam and colleagues solved cryo-EM structures of Pfs48/45, needed for Plasmodium falciparum development, with potent antibodies. The work revealed conformational epitopes, with implications for design of therapies against malaria.

Introducing multiplicity and variation into the components of metal–organic frameworks has emerged as new fascinating directions in reticular chemistry. In this Review, the variances in the framework backbone, functionality and metal, and their leading to sequences of chemical information, are highlighted. Anisotropy in these structures is imposed by the variance and realized along a specific direction.

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

Molecular glues have great potential for drug discovery if they can be systematically discovered. Konstantinidou, et al describe a scaffold-hopping approach using multicomponent reaction chemistry to design molecular glues that induce 14-3- 3σ/ERα formation in cells.

Manufacturing complexities, low yield and stability issues have hampered the clinical translation and scaling-up of immunoliposomes to meet the needs of pharmaceutical-grade products. The authors propose a one-step method of incorporating chimeric nanobodies tagged to hydrophobic linkers into liposomes, allowing targeted delivery of small-molecule anti-cancer drugs to tumours.

CARD9 and CARD11 propagate signaling by nucleating Bcl10 polymerization in immune cells and are both held in an autoinhibited state prior to activation. Here, the authors combine structural, biochemical, and cell-based approaches to reveal the structural basis for CARD9/11 autoinhibition and show that the two proteins are activated through similar but distinct mechanisms.

Doa10/MARCHF6 is a conserved E3 ubiquitin ligase in the endoplasmic reticulum (ER) membrane in eukaryotes, but its molecular mechanism was unknown. The authors combine cryo-EM, computational and biochemical analyses to reveal how Doa10 recognizes its substrate proteins for ER-associated degradation.

Cryo-EM structures of human calcium-sensing receptor reveal intrinsic asymmetry in the receptor homodimer upon activation that is stabilized by calcimimetic drugs adopting distinct poses in the two protomers, priming one protomer for G-protein coupling.

iMARGI (in situ mapping of RNA–genome interactome) is a proximity ligation method for global profiling of chromatin-associated RNAs. A linker sequence bridges DNA and RNA in physical proximity, permitting sequencing library preparation and mapping of DNA–RNA contacts.

Transient receptor potential vanilloid channel 3 (TRPV3) responds to temperature and sensitizes upon repeated stimulation with either heat or agonists. Here authors present the cryo-EM structures of apo and sensitized human TRPV3 and describe the structural basis of sensitization.

This protocol describes solid-phase DNA-encoded library synthesis suitable for various high-throughput screening applications. The libraries are constructed using consecutive on-bead chemical synthesis and DNA encoding ligations, resulting in decodable library beads.

Fluorescent protein reporters based on GFP exist, but have intrinsic disadvantages. Here the authors incorporate pH, Ca²⁺ and protein–protein interaction sensing modalities into de novo designed mini-fluorescence-activating proteins (mFAPs), with increased photostability and smaller size, which bind a range of DFHBI chromophore variants.

SARS-CoV-2 spike-directed, non-neutralizing antibodies were converted into broad-spectrum inhibitors by conjugation to the SARS-CoV-2 receptor, ACE2, resulting in fusion proteins that target all SARS-CoV-2 variants of concern tested.

TWIK1 is a pH-gated K + channel highly expressed in brain and heart that contributes to cardiac rhythm and insulin release. Here, Turney et al. use cryo-EM and electrophysiology to show how TWIK1 gates closed in response to lowered pH through conformational changes centered at the selectivity filter.

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.

Liu, Zhang, Yao et al. report that IRE1 α clustering, known to be part of the unfolded protein response, is membrane-bound phase separation and that IRE1 can coalesce with the phase-separated stress granules.

Lipin/Pah phosphatidic acid phosphatases generate diacylglycerol to regulate triglyceride synthesis and cellular signaling. Here authors determine structures of Tetrahymena thermophila Pah2 and identify an N-terminal amphipathic helix essential for membrane association.

PGAM5 is a mitochondrial protein phosphatase whose functions include regulation of mitophagy and cell death. Here, the authors use x-ray crystallography and EM to show that PGAM5 forms dodecameric rings and filaments in solution, and find that PGAM5 rings are essential for catalysis and for a structural effect PGAM5 has on mitochondrial membranes, independently of catalytic activity.

Interactions between metal-organic frameworks (MOFs) and water are difficult to predict. Here, the authors report a Zn MOF follows two pathways upon water exposure. Characterization of both routes has revealed insights for future rational design.

Deubiquitinases are proteases that cleave after the C-terminus of ubiquitin to hydrolyze ubiquitin chains and cleave ubiquitin from substrates. Here the authors describe a reactive-site-centric chemoproteomics approach to studying deubiquitinase activity, and expand the repertoire of known deubiquitinases.

Andre Berndt and colleagues introduce a machine learning approach to enhance the biophysical characteristics of genetically encoded fluorescent indicators, deriving and testing in vitro new GCaMP mutations that surpass the performance of existing fast GCaMP indicators.

Optical contrast agents using AND-gate logic enhance the specificity and sensitivity of fluorescence-guided imaging in the resection of tumours and in the detection of metastases in mouse models of cancer.

Antisense oligonucleotide (ASO) cellular activity requires endosomal escape. Here, the authors show that disrupting Golgi-endosome protein AP1M1 enhances ASO activity by prolonging ASO endosomal residence and increasing the likelihood of endosomal escape.

Human acetyltransferases MOZ and MORF mediate development programs and are dysregulated in diseases. Here the authors identified two winged helix (WH) domains in MORF/MOZ and characterized their DNA binding functions, including targeting of CpG by WH1.

A single-molecule forced unfolding of E. coli chloride transporter ClC-ec1 shows that the N- and C-terminal halves of the protein unfold independently, with exposed polar surfaces stabilized by membrane lipid head groups and water.

Opposing forces generated by exopolysaccharide trail binding versus type IV pilus retraction generate a high cyclic diGMP–high cyclic AMP state in Pseudomonas aeruginosa that promotes social motility.

The opioid antidote naloxone used to treat opioid overdoses has a short duration of action requiring repeated doses. Here the authors develop an extended release naloxone prodrug delivery system and report the preclinical testing in rat and cynomolgus monkey models.

Enfortumab vedotin (EV) is the current standard treatment for advanced bladder cancer, but resistance typically develops within a year, highlighting the need for new therapies. This study demonstrates that NECTIN4-targeting CAR T cells are effective against bladder cancer, including EV-resistant cells, and their potency can be further enhanced by using rosiglitazone to boost NECTIN4 expression.

Cryo-EM reveals an asymmetric bacterial photosynthetic supercomplex built upon a homodimeric reaction center core. The structure provides mechanistic insights into light excitation transfer and a possible evolutionary transition intermediate of photosynthetic machinery.

Flycatcher1 (FLYC1) is a candidate mechanosensitive channel involved in Venus flytrap touch-induced prey capture. Here, the authors report structural and functional details of FLYC1, with insights into gating conformational transitions.

Volume EM provides connectomic data but lacks necessary molecular information. Here, authors show fluorescent scFvs enable multiplexed immunolabeling and correlated light and electron microscopy, suggesting potential for molecularly annotated connectomic data.

Ryanodine Receptor type 3 mediates ER Ca2+ release in different cell types. Here, the authors use cryo-EM to reveal a binding site for chloride and two distinct sites for ATP. Epileptic encephalopathy mutations are predicted to perturb its function.

Using cryo-EM, Karasmanis, Reimer, and Kendrick et al. reveal a Lis1-mediated dynein dimer, termed Chi, that serves as intermediate state in relieving dynein’s autoinhibition.