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Cryo-electron microscopy structures of the human lysosomal transmembrane protein LYCHOS show that it comprises a transporter-like domain fused to a G-protein-coupled receptor, and that the transporter domain is similar to the plant PIN family.

[NiFe] hydrogenases contain a conserved arginine (R509) that is suspended over the Ni and Fe atoms. Biochemical, crystallographic and electrochemical analysis of an R509K mutant reveal >100-fold lower oxidation activity despite the maintenance of structural integrity.

Complex organisms perceive their surroundings with sensory neurons that encode physical stimuli into spikes of electrical activities. Here a thermosensory chemical neuron based on DNA and enzymes has been reported, which spikes with chemical activity when exposed to cold.

Protein lysine methyltransferases modulate the activities of chromatin and non-chromatin proteins by specific methylation of lysine side chains. A large-scale structure-based design approach has yielded a new chemical probe that potently and selectively inhibits G9a and GLP methyltransferases in cells.

The authors describe the development of ASPIR-1, a small molecule that specifically inhibits AAA proteins by covalently modifying a cysteine residue introduced by mutagenesis at the AAA ATPase site.

Due to the complexity of the protein secretory pathway, strategy suitable for the production of a certain recombination protein cannot be generalized. Here, the authors construct a proteome-constrained genome-scale protein secretory model for yeast and show its application in the production of different misfolded or recombinant proteins.

The cell cycle regulatory E3 ligase APC/C cooperates with UBE2C to prime substrates with ubiquitin and UBE2S to extend the ubiquitin chains. Careful analysis reveals that binding of the UBE2S to APC/C accelerates the rate-limiting step of APC/C–UBE2C.

A deep-learning-based strategy is used to design artificial luciferases that catalyse the oxidative chemiluminescence of diphenylterazine with high substrate specificity and catalytic efficiency.

Cyclohexadienyl dehydratase (CDT) evolved from a cationic amino acid binding protein ancestor without enzymatic activity (AncCDT-1) via a series of intermediates. Here, the authors combine EPR, X-ray crystallography and MD simulations to study the structural dynamics of these evolutionary intermediates and observe that they predominantly populate catalytically unproductive conformations, while CDT exclusively samples catalytically relevant compact states, and which reveals how the conformational landscape changes along the evolutionary trajectory.

Readily synthesized maltose–neopentyl glycol (MNG) amphiphiles are useful reagents for stabilizing, extracting and crystallizing a variety of integral membrane proteins and have favorable properties relative to conventional detergents.

Methylphenidate, the active compound in Ritalin, is used to treat attention and hyperactivity disorders, but it is also taken for recreational use. Calipari et al.show that high-dose methylphenidate leads to enhanced dopaminergic responses to amphetamines, and enhanced amphetamine-seeking behaviour in rats.

EZH2 is a protein methyltransferase component of the polycomb repressive complex 2 (PRC2) that installs the H3K27me3 chromatin mark. EPZ005687 inhibits EZH2 function and H3K27 trimethylation in cells and selectively kills lymphoma cells that require EZH2 for proliferation.

Marine Proteobacteria use the β-hydroxyaspartate cycle to assimilate glycolate, which is secreted by algae on a petagram scale, providing evidence of a previously undescribed trophic interaction between autotrophic phytoplankton and heterotrophic bacterioplankton.

Single-molecule assays show that the recruitment of UvrA and UvrAB to Mfd–RNA polymerase complex formed on a DNA lesion arrests the translocating complex and causes its dissolution.

Here, Robert-Paganin et al. show that myosin A from Plasmodium falciparum is critical for red blood cell invasion and that non-canonical interactions and regulated phosphorylation are important for force generation during parasite invasion.

Cardiac organoids incorporating an oxygen-diffusion gradient and stimulated with the neurotransmitter noradrenaline can model the structure and function of the human heart after myocardial infarction.

Laboratory evolution of the bacterial transpeptidase sortase A coupled with yeast display selection enables a change of the enzyme’s substrate preference to recognize and covalently label endogenous amyloid-β protein, impeding the protein’s ability to aggregate.

The mechanism of glycogenesis, initiated by glycogenin, involves three distinct kinetic phases, with the final phase involving a refining process where only glucose is tolerated as a substrate.

It is unclear why atmospheric O₂ remained at low levels for >1.5 billion years following the Great Oxidation Event. Here, the authors show that tectonic recycling of previously accumulated sedimentary organic carbon, and oxygen sensitivity of its oxidative weathering stabilized O₂at ∼1–10% of present levels.

Jun Yang and colleagues perform targeted sequencing of NUDT15 and identify loss-of-function variants associated with thiopurine intolerance. Functionally, they show that NUDT15 inactivates thiopurine metabolites, providing a mechanism to explain the association between NUDT15 loss-of-function variants and thiopurine toxicity.

Microbial pathways can be engineered for the sustainable production of chemical products such as transportation fuels. Here the authors design and implement a de novo biosynthetic pathway in E. colithat is capable of producing the gasoline replacement, 4-methyl-pentanol.

The lysosomal storage disease mucopolysaccharidosis I is treated with recombinant α-L-iduronidase but production of the enzyme is expensive. In this study, α-L-iduronidase is compartmentalized within the endosperm of maize via a unique mRNA strategy yielding the active, correctly glycosylated protein.

Coupling distances between synaptic vesicles and Ca²⁺ channels determine the efficacy of neurotransmission. Böhme et al. find that presynaptic scaffold complexes spatiotemporally control Unc13 isoforms to establish two independent release pathways at subsynaptic active zones: Unc13B defines nascent, loosely coupled synapses whereas Unc13A facilitates release at mature synapses by tight coupling between Ca²⁺ channels and synaptic vesicles.

Mesalamine, the gold-standard ulcerative colitis treatment, rapidly decreases polyphosphate levels in bacterial members of the gut microbiome, sensitizing them towards oxidative stress and reducing colonization and persister cell and biofilm formation.

Clinical trials of BAFF blockade with belimumab have shown partial efficacy for the treatment of systemic lupus erythematosus (SLE), so other therapeutic options are required. Here, the authors present a new small molecule inhibitor that targets NIK with a similar efficacy to BAFF inhibition in two mouse models of SLE.

Catabolizing lignin-derived aromatic compounds requires an aryl-O-demethylation step. Here the authors present the structures of GcoA and GcoB, a cytochrome P450-reductase pair that catalyzes aryl-O-demethylations and show that GcoA displays broad substrate specificity, which is of interest for biotechnology applications.

A ring ATPase from a bacteriophage, ϕ29, helps load the dsDNA genome into the viral shell. It is shown that this motor packages the DNA in 10 base pair (bp) bursts, which are composed of four individual 2.5 bp steps, each representing hydrolysis of a single ATP. Such a non-integral step size is unexpected, and raises intriguing mechanistic questions about ATP hydrolysis within rings.

Estimates of stomatal conductance are important for models of crop and ecosystem water and carbon flux. Here, data from temperate tree species show interspecific variation in stomatal function that can be accounted for to make models more accurate.

An enzyme (AspRedAm) capable of coupling carbonyls with a variety of amines in a reductive amination has now been discovered. Kinetic studies revealed that the enzyme catalysed both the imine formation step, as well as the reduction step. Structure and mutagenesis studies have highlighted essential catalytic residues and preparative scale examples have demonstrated total turnover numbers of up to 32,000.

Lytic polysaccharide monooxygenases (LPMOs) are a class of copper-dependent enzymes that oxidatively degrade polysaccharides and find use in industrial processing of lignocellulose. Crystallographic and spectroscopic studies define how LPMOs recognize their oligosaccharide substrates and mediate oxidative cleavage.

The bacterial zinc transporter ZntB is important for maintaining zinc homeostasis and is mechanistically not well understood. Here, the authors present the cryo-EM structure of ZntB at 4.2 Å resolution, perform transport assays and propose a model for its Zn²⁺ transport mechanism.

Aromatic amines can form covalent DNA adducts, in which the damaged base can cause mutations in the vicinity of the lesion. A mechanism for such semi-targeted mutagenesis is now proposed, based on structural and functional data on Dpo4: the bulky lesion-bypass polymerase interaction leads to a conformation of Dpo4 that stabilizes misaligned intermediates.

A chemically synthesized analog of Bacillus cereus secondary cell wall polysaccharide (SCWP) facilitates the identification of PatB1 as a SCWP O-acetyltransferase, and the structure of PatB1 provides insights into its catalytic mechanism.

Minogue et al. show that glutarate, a metabolite derived from tryptophan catabolism, has the ability to shape anti-tumour T cell responses by modulating pyruvate handling and alpha-ketoglutarate-dependent dioxygenases.

In this work, authors aim to optimize the dosing of TBI-223, a novel oxazolidinone for tuberculosis, using a translational platform which incorporates preclinical and clinical trial data.

The introduction of fluorine into a drug molecule can alter the biological responses to it, including modulating bioavailability, pharmacokinetics and selectivity. Now, a hybrid polyketide/fatty acid synthase multienzyme has been designed to incorporate fluorinated precursors during polyketide biosynthesis in an approach that provides new chemoenzymatic access to fluorinated natural compounds.

Cystathionine beta-synthase is a conserved essential enzyme of one-carbon metabolism. Here, the authors show that the enzyme oligomerises to form filaments that undergo conformational and morphological changes in response to its activator S-adenosyl-L-methionine, the global methyl donor.

A microfluidic intestine-on-a-chip that allows the control of physiologically relevant oxygen gradients, enables the extended coculture of living human intestinal epithelium with stable communities of aerobic and anaerobic human gut microbiota.

Biological degradation of glycosides involves, alongside hydrolysis, β-elimination for glycosidic bond cleavage. Here, the authors report an O-glycoside β-eliminase from Agrobacterium tumefaciens that converts the C3-oxidized O-β-d-glucoside of phloretin into the aglycone and the 2-hydroxy-3-keto-d-glycal elimination product, and suggest convergent evolution of β-eliminase active sites for the cleavage of natural product 3-keto-O-glycosides.

One-carbon compounds, including carbon dioxide and methane, represent a sustainable resource for chemical conversions. This Review highlights recent advances in the biochemical upgrading of one-carbon substrates to value-added products using a combination of cellular, cell-free and abiotic catalysis strategies.

Here the authors screen a saturation mutagenesis library of the disordered N-terminal tail of the actin severing protein cofilin. Their results reveal how a key phosphorylation site can balance competing sequence constraints on function and regulation.

Serial synchrotron crystallography reveals the structure of the human glycine transporter GlyT1, showing how a state-specific inhibitor exerts its effects, and potentially informing the design of new GlyT1 inhibitors to treat a range of disorders of the central nervous system.

TGFβ can promote the development of drug resistance and growth of multiple myeloma (MM). Here the authors report the results of a phase 1b trial of the TGFβ type I receptor kinase inhibitor vactosertib in combination with pomalidomide in patients with relapsed and/or refractory (MM) who had received >2 lines of chemoimmunotherapy.

Phage display reveals peptides that bind to the caspase-6 zymogen, inducing its tetramerization and specifically inhibiting its enzyme activity both in vitro and in neuronal cells.