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Calcium and redox signalling have important roles in acclimation processes. Here, the authors characterise a protein from Chlamydomonas reinhardtiithat can integrate calcium and redox-related signalling.

The COP9 signalosome (CSN) complex regulates cullin–RING E3 ubiquitin ligases—the largest class of ubiquitin ligase enzymes, which are involved in a multitude of regulatory processes; here, the crystal structure of the entire human CSN holoenzyme is presented.

Directed evolution has emerged as a powerful tool for the identification of improved enzyme catalysts. Now, gel-shell beads are introduced as compartments that cage an enzyme with its encoding DNA, constituting a new genotype–phenotype linkage. Screening of 10⁷ gel-shell beads by flow cytometry leads to an improved phosphotriesterase bioremediation catalyst.

Michal Olszewski et al. demonstrate the collaboration of Cdc48 and the 26S proteasome in degrading ubiquitinated, well-folded proteins that lack unstructured segments. This study suggests that Cdc48 creates flexible initiation regions in compact substrates for their proteasome-mediated degradation.

Lipoproteins are essential components of bacterial membranes. Here the authors present the crystal structures ofPseudomonas aeruginosa and Escherichia coliapolipoprotein N-acyltransferase, which catalyses the final step in the lipoprotein synthesis pathway, and give insights into its mechanism.

Activation of an LTR retrotransposon inserted upstream of the Fgf8 gene produces viral-like particles in the mouse developing limb, triggering apoptosis and causing limb malformation. This phenotype can be rescued by mutations in the retrotransposon coding sequence.

A combination of structural and protein-chemistry approaches along with phylogenetic analyses provide insights into the specific activities of mouse tubulin tyrosine ligase-like enzymes as initiases or elongases of glutamylation.

Experimental data on enzyme turnover numbers is sparse and noisy. Here, the authors use machine learning to successfully predict enzyme turnover numbers for E. coli, and show that using these to parameterize mechanistic genome-scale models enhances their predictive accuracy.

Ubiquitin modification also occurs in archaea. Here, the authors characterize an archaeal ancestral ubiquitination system, present the crystal structure of the archaeal deubiquitinase Rpn11 from Caldiarchaeum subterraneum bound to ubiquitin and provide insights into evolutionary relationships.

The 3CL protease of SARS-CoV-2 is inhibited by PF-00835231 in vitro. Here, the authors show that the prodrug PF-07304814 has broad spectrum activity, inhibiting SARS-CoV and SARS-CoV-2 in mice and its ADME and safety profile support clinical development.

Plant pathogens translocate type III effector (T3E) proteins that may be recognized by plants to trigger immunity. Here, the authors show that the Xanthomonas T3E XopH possesses a novel 1-phytase activity that is required for XopH-mediated immunity of plants carrying the Bs7 resistance gene.

The chemical synthesis of nucleoside analogues with modifications at the 2-position often requires multiple steps and the extensive use of protecting groups. Now, biocatalytic cascades are reported for the synthesis of 2-functionalized sugars and 2′-functionalized nucleosides, using enzymes derived from those of the purine nucleoside salvage pathway.

Pseudouridine (Ψ), the C-nucleoside isomer of uridine, and its 1-N-methyl derivative, are incorporated in mRNA vaccines and essential for their efficiency, but difficult to synthetically access. Here, the authors report on selective and atom-economic 1N-5C rearrangement of β-d-ribosyl on uracil to obtain Ψ from unprotected U in quantitative yield

A genome-wide CRISPR interference screen shows that a signalling pathway involving OMA1, DELE1 and the eIF2α kinase HRI relays mitochondrial stress to the cytosol to trigger the integrated stress response.

Aminoglycoside resistance is predominantly mediated by enzymatic modification, wherein resistance enzymes typically bind the antibiotics in a low-energy conformation that closely mimics their ribosome-bound state. Here, the authors reveal that AAC(3)-Ia and AAC(3)-XIa deviate from this strategy by binding aminoglycosides in a unique, strained conformation, suggesting alternative mechanisms for antibiotic resistance.

Affinity chromatography allows for the separation of biomolecules such as proteins, based on a change in the chemical solvent composition and the resulting impacts on ligand binding. Here, authors introduce a physical principle by exploiting the light-dependent interaction between the Azo-tag and an α- CD chromatography matrix.

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.

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.

Transcription can pose a threat to genomic instability through the formation of R-loops, which are RNA–DNA hybrids with a displaced non-template DNA strand. Here the authors mapped the R-loop proximal proteome in human cells and identified a role of the tumor suppressor DDX41 in opposing R-loop and double strand DNA break accumulation in gene promoters.

Inhibitors of mitochondrial transcription that target human mitochondrial RNA polymerase provide a chemical biology tool for studying the role of mitochondrial DNA expression in a wide range of pathologies.

Rescue of ribosomes stalled on non-stop mRNA is essential for cell viability, and several rescue systems to resolve stalling exist in bacteria. Here, the authors use rapid kinetics and cryo-EM to reveal the pathway and selectivity mechanism of ArfB-mediated ribosome rescue.

The PSA (KLK3) genetic variant rs17632542 is associated with reduced prostate cancer risk and lower serum PSA levels, although the underlying reasons are unclear. Here, the authors show that this PSA variant reduced proteolytic activity and leads to smaller tumours, but also increases invasion and bone metastasis, indicating its dual risk association depending on tumour context; the variant is associated with both lower risk and poor clinical outcomes.

Mercury isotope signatures in groundwater, soil gas, solid peat, and atmosphere suggest that dark abiotic reduction of peat soil Hg^II to volatile Hg⁰ does not play a significant role in mobilizing Hg during peat mass loss

Alien species of animals and plants can invade new regions of the earth. This study performs a global analysis of temporal dynamics and spatial patterns of alien species introductions over the past 200 years, and reports no saturation in the rate at which these invasion are increasing.

Here the authors present a syntrophic vesicle system for selective transport of adenine nucleotides between ATP-producing and ATP-consuming nanoreactors. The platform can sustain synthetic cells, bionanoreactors and life-like entities with ATP.

Microsporidia are obligate intracellular parasites that infect both humans and animals. Here, Dean et al. perform ancient gene reconstruction and functional assays to investigate the evolution and functional diversification of nucleotide transporters which are key to the parasite's intracellular lifestyle.

Bacterial cell wall components are assembled in a transmembrane cycle that involves the membrane integral pyrophosphorylase, BacA. Here the authors solve the crystal structure of BacA which shows an interdigitated inverted topology repeat that hints towards a flippase function for BacA.

X-ray crystallographic analyses of KDM5B provide a view of the enzyme's iron(II)- and 2-oxoglutarate-containing catalytic core, and structures of KDM5B complexes with small-molecule inhibitors reveal selectivity profiles for multiple compound chemotypes.

Cysteine hydropersulfides (CysSSH) are believed to have a cellular redox protective role. Here the authors show that these species can be produced from L-cysteine by cysteinyl-tRNA synthetases and that these enzymes are also involved in mitochondrial biogenesis and bioenergetics 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.

Glycolytic enzymes are challenging drug targets due to their highly conserved active sites and phosphorylated substrates. Here, the authors identify fast acting allosteric inhibitors of Trypanosoma brucei phosphofructokinase that block trypanosome glycolysis and provide cure evidence in murine model.

How is acetyl-CoA produced in the context of the endogenous, eukaryotic pyruvate dehydrogenase complex metabolon? Here the authors dissect the embedded transacetylase reaction through biochemical, cryo-EM, HADDOCKing and molecular dynamics methods.

Acyltransferase activity of the enzyme bile salt hydrolase is identified and shown to mediate microbial bile acid conjugation, diversifying the bile acid pool and expanding their role in gut physiology.

The paper presents the universal QM-based scoring function that accurately and rapidly predicts protein-ligand binding affinities, outperforming current computational tools. This is demonstrated on the PL-REX experimental benchmark dataset.

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.

Mutations in glucocerebrosidase (GCase) cause the lysosomal storage disorder Gaucher’s disease and are the most common risk factor for Parkinson’s disease. Using a fusion protein comprising GCase and a transferrin receptor antibody fragment, the authors show that the transferrin receptor pathway can be therapeutically exploited to both pass the blood-brain barrier and efficiently target lysosomal GCase deficiency.

Antiviral drugs are seen as essential requirements for control of initial influenza outbreaks caused by a new virus. This paper presents enzymatic properties and crystal structures of neuraminidase mutants from H5N1 infected patients that explain the molecular basis of observed resistance against the neuraminidase inhibitor Oseltamivir.

The ability to induce metabolic pathways in response to a changing environment is an important component of bacterial fitness. Bartl et al. identify optimal programmes for metabolic pathway activation depending on protein synthesis capacity constraints, and demonstrate their impact on operonic organization.

The transplantation of residues from a selective to a nonselective haloalkane dehalogenase yields the correct active site geometry but not function. Computational and biophysical results explain this disparity, showing that the dynamics and hydration of the engineered protein match its parent, not its target.

A major carbohydrate transporter, GpMST1, is characterized by exploiting the symbiosis between Geosiphon pyriformis and the cyanobacterium Nostoc punctiforme.

The parasite Encephalitozoon cuniculi contains mitosomes instead of functional mitochondria. Although mitochondrial carrier proteins are known to be responsible for ATP transport from the mitochondria to the cytosol, Hirt et al. now show this process to be reversed in E. cuniculi, where ATP appears to be transported from the cytosol to the organelle.

The development of selective ubiquitin-specific protease-7 (USP7) inhibitors GNE-6640 and GNE-6776, which induce tumour cell death and reveal differential kinetics of Lys-48 and Lys-63-linked ubiquitin chain depolymerization by USP7.