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BindCraft, an open-source, automated pipeline for de novo protein binder design with experimental success rates of 10–100%, leverages AlphaFold2 weights to generate binders with nanomolar affinity without the need for high-throughput screening.

The molecular mechanism between each progesterone receptor (PR) isoform and oncogenic co-regulators SRC3 and p300 is poorly understood. Here, the authors report PR isoform-specific interactions with these co-regulators and antagonist-driven protein interactions, challenging the classical model of nuclear receptor activation.

The antiviral dsRNA sensor PKR is regulated by PACT. This paper shows how PACT prevents aberrant PKR activation by endogenous dsRNAs like Alu. PACT disrupts PKR’s dsRNA scanning without blocking its binding, resetting its activation threshold to tolerate cellular dsRNA and preserve homeostasis.

The Hsp70/Hsp40 system plays an important role in maintaining cellular proteostasis but so far it is not well understood how Hsp70 proteins are recruited to specific Hsp40 co-chaperones. Here, the authors combine biochemical and biophysical approaches to characterise the oligomeric mammalian Hsp40 DnaJB8. They identify an intra-oligomer DnaJB8 interaction between the N-terminal J-Domain and the C-terminal domain that occludes the J-Domain surface that binds Hsp70 and propose a model for DnaJB8-Hsp70 recruitment.

The mechanism of flavivirus activation for membrane fusion is not yet understood. Here, Vaney et al. describe how the viral pr protein, derived from an HSP40/DnaJ chaperonin, interacts with a pH sensing loop in the envelope protein E for fusogenic activation.

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.

The development of IDH variant inhibitors is a breakthrough as it is the first time metabolism has been successfully targeted by small molecule drugs in cancer. Here the authors report studies on resistance to the pioneer drug ivosidenib leading to identification of inhibitors retaining activity.

HER2 acts an oncogenic driver in numerous cancers. Here, the authors design an anti-HER2 biparatopic and tetravalent IgG fusion with inhibitory effects in a xenograft model.

Metagenomic analysis has uncovered a previously uncharacterized clade of Rubisco related to form I Rubisco found in plants and cyanobacteria. Structural and kinetic data show how this proto-form I Rubisco assembles and functions without small subunits.

Here, the authors combine three different antibody specificities and an Fc domain on a single multivalent molecule, resulting in high neutralization activity despite viral sequence variability.

Most enzymes involved in plant natural products biosynthesis remain uncharacterized. Here, the authors establish a screening pipeline and apply it to family 1 glycosyltransferases to reveal their promiscuity and preference for planar, hydroxylated aromatic substrates.

The Tousled-like kinase (TLKs) family belongs to a distinct branch of Ser/Thr kinases that exhibit the highest levels of activity during DNA replication. Here the authors present the crystal structure of the kinase domain from human TLK2 and propose an activation model for TLK2 based on biochemical and phosphoproteomics experiments.

X-ray crystallographic analysis reveals features of the tandem catalytic domains of histone deacetylase 6 (HDAC6), their inhibition by small molecules and functional insights into the enzyme's role in tubulin deacetylation.

Wyatt et al. explore glycaemic responses after a standardized meal and find that postprandial glycaemic dip is a predictor of hunger and subsequent energy intake.

A connectome of the right optic lobe from a male fruitfly is presented together with an extensive collection of genetic drivers matched to a comprehensive neuron-type catalogue.

Schief and colleagues show that germline-targeting epitope scaffolds can elicit responses from rare broadly neutralizing antibody precursor B cells with predefined binding specificities and genetic features.

Structural, biophysical and genetic analyses reveal that Schizosaccharomyces pombe Ctp1 forms a flexible tetramer with multivalent DNA-binding and bridging activities that contribute to Ctp1's role in repair of DNA double-strand breaks.

The AKAP79 scaffold protein couples plasma membrane Ca²⁺ influx in neurons to activation of calcineurin, which in turn activates NFAT. Analysis of this interaction shows that AKAP79 and NFAT bind the same interface on calcineurin, but the affinity of the calcineurin-AKAP79 interaction is finely balanced to promote calcineurin recruitment to the scaffold while still allowing calcineurin release for NFAT activation.

FAN1 is a structure-specific nuclease that plays a major role in eliminating highly cytotoxic interstrand DNA crosslinks. Here, Zhao et al. present several crystal structures of FAN1 in complex with DNA substrates and biochemical analyses that establish how FAN1 functions to resolve interstrand DNA crosslinks.

Two malaria vaccines comprising Plasmodium falciparum sporozoites and treatment with either pyrimethamine or chloroquine induced durable protective responses against both the African vaccine strain and a heterologous South American strain of P. falciparum.

The condensation of RNA polymerase II (Pol II) into transcriptionally active clusters is critical for eukaryotic gene regulation and pre-mRNA transcription. Here the authors show that a tight network of tyrosine-proline interactions imparts temperature and concentration-dependent self-coacervation of Pol II’s C-terminal domain (CTD).

Rhizoclosmatium globosum contains three rhodopsin-guanylyl cyclases (RGCs) predicted to enable visual orientation of zoospores. Here authors show that RGC1 and 2 function as light-activated cyclases only upon heterodimerization with RGC3 (NeoR), a near-infrared absorbing, highly fluorescent rhodopsin.

Acyl protein thioesterase APT2 interacts with membranes via its charged β-tongue, becomes palmitoylated by ZDHHC3/7 and deforms the bilayer to extract substrate acyl chains. APT2 deacylation leads to its membrane release and degradation.

The mechanisms of Z-ring assembly and regulation in bacteria are poorly understood, particularly in non-model organisms. Here, Sogues et al. study the interaction between FtsZ and SepF in Corynebacterium glutamicum, showing an essential interdependence of these proteins for formation of a functional Z-ring.

In this study, Aggarwal and colleagues perform prospective sequencing of SARS-CoV-2 isolates derived from asymptomatic student screening and symptomatic testing of students and staff at the University of Cambridge. They identify important factors that contributed to within university transmission and onward spread into the wider community.

The activity of CAR-T cells is reversibly halted with a small-molecule drug.

Long polyynes have fascinating properties but they are difficult to synthesize as a consequence of their high reactivity. Now, it has been shown that cobalt carbonyl complexes can be used as masked alkyne equivalents, enabling the preparation of stable polyyne polyrotaxanes with up to 34 contiguous triple bonds.

Shifts in species’ migration timing as a result of climate change can result in mismatched temporal overlap with their critical resources. Here the authors show that the magnitude and direction of shifts in juvenile Pacific salmon migration timing vary among species and populations, resulting in variable mismatch with marine productivity, which has implications for climate change vulnerability.

The Omicron variant evades vaccine-induced neutralization but also fails to form syncytia, shows reduced replication in human lung cells and preferentially uses a TMPRSS2-independent cell entry pathway, which may contribute to enhanced replication in cells of the upper airway. Altered fusion and cell entry characteristics are linked to distinct regions of the Omicron spike protein.

A study of the evolution of the SARS-CoV-2 virus in England between September 2020 and June 2021 finds that interventions capable of containing previous variants were insufficient to stop the more transmissible Alpha and Delta variants.

An international consortium reports the genomic sequence for ten Drosophila species, and compares them to two other previously published Drosophila species. These data are invaluable for drawing evolutionary conclusions across an entire phylogeny of species at once.

Yu et al examined a panel of both experimental and clinically-relevant TNF agonists in order to advance our understanding of the mechanisms underlying their varying activities and anti-tumor responses. They demonstrated that agonists with greater activity induced higher density receptor clustering and specific super-structures as opposed to simply larger receptor clusters.

The PREDICT 1 trial shows large inter-individual variations in postprandial metabolic responses to standardized meals in over 1,000 participants, demonstrating potential for development of personalized nutrition strategies.

Genomic, epigenomic and transcriptomic data derived from the Mediterranean amphioxus (Branchiostoma lanceolatum) provide insights into the evolution of the genomic regulatory landscape of chordates.

Post-international travel quarantine has been widely implemented to mitigate SARS-CoV-2 transmission, but the impacts of such policies are unclear. Here, the authors used linked genomic and contact tracing data to assess the impacts of a 14-day quarantine on return to England in summer 2020.

Predictions suggest that a high proportion of plant species will be threatened with extinction in the near future. A global assessment of the threat status of cacti suggests that these iconic plants are amongst the most threatened taxonomic groups, with 31% of the 1,478 evaluated species at risk of extinction.

Genetic and testing data from England show that the SARS-CoV-2 variant of concern B.1.1.7 has a transmission advantage over other lineages.

Chronic infection with SARS-CoV-2 leads to the emergence of viral variants that show reduced susceptibility to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma.

Sera from vaccinated individuals and some monoclonal antibodies show a modest reduction in neutralizing activity against the B.1.1.7 variant of SARS-CoV-2; but the E484K substitution leads to a considerable loss of neutralizing activity.

Analysis of the cell surface proteome (surfaceome) is essential for cell classification but is technically challenging. Here the authors miniaturize and automate the Cell Surface Capture method to increase sensitivity, reproducibility and throughput, and use it to create population-specific surfaceome maps of developing mouse B cells.

A novel platform for vaccines has been developed using self-assembling ferritin-based nanoparticles displaying influenza virus haemagglutinin; the haemagglutinin–nanoparticle vaccine induces more broad and potent neutralizing antibodies against diverse virus strains than a licensed influenza vaccine in mice and ferrets.

The crystal structure of sperm-expressed surface protein SPACA6 shows similarities to IZUMO1 though their functions are not redundant. Structural homology search in the AlphaFold human proteome and sequence search suggest a superfamily of mammalian gamete fusion-associated proteins.

Building crystal structures into the electron density is an important step in protein structure solution. Here, the authors recruit online game players, students, and experienced crystallographers to compete in a competition to solve a new structure, and find that crowdsourcing model-building works.

The atmospheres of white dwarfs often contain elements heavier than helium, even though these elements would be expected to settle into the stars’ interiors; observations of the white dwarf WD 1145+017 suggest that disintegrating rocky bodies are orbiting the star, perhaps contributing heavy elements to its atmosphere.

A microfluidics approach that links short sequence reads enables haplotype construction and complex variation identification from tiny amounts of input DNA.

Cell surface proteins contribute to neuronal development and activity-dependent synaptic plasticity. Here, the authors perform a time-resolved surfaceome analysis of developing primary neurons and in response to homeostatic synaptic scaling and chemical long-term potentiation (cLTP), revealing surface proteome remodeling largely independent of global proteostasis.