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Proteins contain modular structural and functional units called domains. Here, the authors have developed Merizo, a deep learning method for domain segmentation applicable to experimental structures as well as those generated by AlphaFold2.

Bai and colleagues present MapDiff, a discrete diffusion-based framework for generating amino acid sequences conditioned on a target protein structure, with strong performance in predicting uncertain regions and achieving high in silico foldability.

Deep learning enables large-scale protein structure prediction, yet linking structure to function remains a challenge. Here, the authors use topology to reveal fundamental organising features of the protein universe, providing insights into domain architecture, binding sites, evolution, and disease.

Bayesian Flow Networks generate diverse, novel, and coherent protein sequences, surpassing prior unconditional generation methods. They also permit flexible conditional generation during inference, which is demonstrated on antibody inpainting tasks.

DNA methyltransferase MET1 maintains CG methylation in plants. Kikuchi determined the cryo-EM structure of Arabidopsis MET1, revealing autoinhibition and activation mechanisms, with conserved and plant-specific features distinct from mammalian DNMT1.

This study integrates ribosome profiling, single molecule methods and computational predictions to reveal that molecular chaperones bind ‘unsatisfied’ residues exposed on partial nascent folds, rationalizing how their activities generate a robust co-translational protein folding network.

The folding of protein domains can occur concomitant with their synthesis, and the rates at which individual codons are translated by the ribosome can affect the folding process. Here the authors present a kinetic model that accurately predicts the probability that a nascent protein domain will co-translationally fold in vivo.

The validation of inhibitors targeting PurF, a novel drug target for tuberculosis drug discovery, is described.

A cryo-electron microscopy reconstruction of the virus ΦcrAss001 provides insights into the functions of the viral gene products in capsid assembly and infection.

This study documents the evolution of antibiotic resistance and major growth defects in Yersinia enterocolitica in a patient over 14 years, revealing genetic changes that shed light on bacterial adaptation to infection and therapy.

The diverse Heliconius butterflies have evolved key innovations, including pollen feeding, and are a quintessential example of adaptive radiation. Using comparative genomics, Cicconardi et al. identify targets of selection at coding and non-coding loci during major ecological transitions in Heliconius.

The involvement of cAMP-dependent regulation of HCN4 in the chronotropic heart rate response is a matter of debate. Here the authors use a knockin mouse model expressing cAMP-insensitive HCN4 channels to discover an inhibitory nonfiring cell pool in the sinoatrial node and a tonic and mutual interaction between firing and nonfiring pacemaker cells that is controlled by cAMP-dependent regulation of HCN4, with implications in chronotropic heart rate responses.

Genome-wide analyses identify 30 independent loci associated with obsessive–compulsive disorder, highlighting genetic overlap with other psychiatric disorders and implicating putative effector genes and cell types contributing to its etiology.

EzMechanism is a tool for automated prediction of the catalytic mechanisms of enzymes using their three-dimensional structures and chemical reactions as input.

Family 1 glycosidases (GH1) are present in the three domains of life and share classical TIM-barrel fold. Structural and biochemical analyses of a resurrected ancestral GH1 enzyme reveal heme binding, not known in its modern descendants. Heme rigidifies the TIM-barrel and allosterically enhances catalysis.

Whether antigen processing and presentation differs between pathogen-derived antigens and self-antigens is not clear. Here the authors use a reductionist cell-free approach to study antigen processing, uncovering differences in antigen sensitivity to digestion by cathepsins and resistance to DM.

The central dogma of molecular biology requires many proteins, but how these proteins arose during evolution remains unclear. Here, authors reveal that a subset of RNA polymerases and ribosomal proteins featuring four distinct β-barrel folds diversified from a common ancestor.

The interplay between blood vessel (BV) and epithelial tissue is crucial for organogenesis. Here, the authors co-culture hiPSC-derived liver progenitors on artificial BV to establish functional human bile ducts for modeling congenital biliary disease.

Nissley and co-workers predict protein misfolding into kinetically trapped, entangled conformations that can bypass the proteostasis network to remain soluble but less-functional for long timescales is widespread within the E. coli proteome.

High-throughput sequencing and artificial intelligence-driven structural biology have vastly expanded our understanding of the human metagenome, yet microbial functions remain largely elusive. In this Review, metagenomics analysis is explored across taxonomic, genetic, structural and spatial–temporal dimensions, highlighting emerging tools and opportunities to decode microbial roles in health and disease.

Given the amino-acid sequence or 3D structure of a protein, how much can we predict about its function using just a desktop computer? The recent explosive growth in the volume of sequence data and advancement in computational methods has put more tools at the biologist's disposal than ever before.

Collision cross sections (CCS) from ion mobility mass spectrometry provide information about protein shape and size. Here, the authors develop an algorithm to predict CCS and integrate experimental ion mobility data into Rosetta-based molecular modelling to predict protein structures from sequence.

In an interim phase 1 trial analysis, escalating doses of off-the-shelf allogeneic anti-BCMA CAR T cells, in combination with an anti-CD52 antibody-containing lymphodepletion regimen, were feasible to administer and exhibited an encouraging safety profile in patients with relapsed or refractory multiple myeloma

It has been predicted that mobilization of resistance genes from plasmid to chromosome is selected by an antibiotic pressure. Here, authors discover an antiplasmid system promoting the chromosomal integration of the carbapenemase gene bla_OXA-48.

Computational protein design uses information on the constraints of the biological and physical properties of proteins for protein engineering and de novo protein design. In this Primer, Albanese et al. give an overview of the guiding principles of computational protein design and its considerations, methods and applications and conclude by discussing the future of the technique in the context of rapidly advancing computational tools.

When cells are starved, the enzyme TOR is inhibited, inducing autophagy. In this process, autophagosomes sequester intracellular components and then fuse with lysosomes, producing autolysosomes in which cargo is degraded to regenerate nutrients. Now, a mechanism is revealed by which lysosomes are re-formed. When starvation conditions are prolonged, mTOR is re-activated; this attenuates autophagy and results in tubules and vesicles extruding from the autolysosome and maturing into functional lysosomes.