Search

Despite the existence of many N–N-containing natural metabolites, little is known about the enzymatic mechanisms of N–N bond formation. Now, a catalytically relevant X-ray crystal structure of an N–N-bond-forming enzyme, PipS, is reported and detailed insights into its catalytic mechanism are provided.

C₂H₄ is one of the most important chemical raw materials. Here, the authors report that tuning of pore structure shifts the multi-component gas separation function, enabling one-step production of high-purity C₂H₄ in the quaternary mixture.

The fundamental discovery deepens scientists’ understanding of chemical bonding.

The study reveals a ‘chemocentric’ strategy for identifying charged molecular glue degraders, through discovering a bromodomain-binding molecular glue degrader prodrug that is metabolically activated in cells to recruit the YPEL5-CTLH E3 ligase.

Petroleum-based adhesives are used ubiquitously in daily life and therefore contribute to persistent waste generation. Here the authors synthesize a robust and strong poly(ester amide) adhesive that can be derived from biomass feedstocks and chemically recycled at the end of its life.

Characterization of the heme-dependent enzyme KtzT reveals it to be the elusive enzyme responsible for nitrogen–nitrogen bond formation during the biosynthesis of piperazate, a building block for some nonribosomal peptide natural products.

Pyridoxal 5-phosphate (PLP) is an essential coenzyme involved in diverse amino acid transformations. The discovery that Ind4 catalyzes the PLP-dependent oxidation of an unactivated carbon of L-arginine, as a part of the indolmycin biosynthetic pathway, expands the scope of reactions facilitated by PLP-dependent enzymes.

DNA damage burden and inadequate repair in CUX2⁺ cortical layer 2/3 excitatory neurons contributes to selective vulnerability in neuroinflammatory injury.

Molecular glue degraders have consistently been discovered retrospectively, despite their increasing importance. Herein, a high-throughput approach is described that modifies existing ligands into molecular glue degraders.

Tiny protein crystals often evade X-ray methods. Here, authors solved the seed protein crambin at 0.85 Å by ab initio MicroED from 58 self-formed nanocrystals on standard 200 kV hardware, resolving hydrogen atoms using anisotropy-aware merging.

Negamycin is a decades-old antibiotic that can promote readthrough of premature stop codons and possesses a structure that contains an unusual N–N bond. Now, the long-mysterious negamycin gene cluster has been identified and characterized to reveal a heme-dependent enzyme that directly couples glycine and nitrite to form the N–N linkage.

A molecular glue induces CRBN homodimerization and degradation through degron mimicry, revealing a distinct glue mechanism and offering a tool to study CRBN biology.

MK-7762 is a new oxazolidinone antitubercular agent that is structurally similar to linezolid, and demonstrated in vivo efficacy, lesion penetration and limited toxicity compared to linezolid, indicating it could be used in broad tuberculosis regimens.

The transcription factor ATF4 and its effector lipocalin 2 (LCN2) have a key role in immune evasion and tumour progression, and targeting the ATF4–LCN2 axis might provide a way to treat several types of solid tumour by increasing anti-cancer immunity.

KRAS is an oncogene that switches between a GDP-bound inactive state and a GTP-bound active state. Recently developed KRAS G12C inhibitors are specific to the GDP-bound inactive state. Here, the authors develop a class of covalent KRAS G12C inhibitors capable of targeting both states for the treatment of KRAS-driven cancer.

Although biosynthetic pathways of selenium-containing macromolecules have been known for decades, pathways for specific incorporation of selenium into small molecules have only recently begun to be uncovered. Now the selenometabolome is expanded further through the discovery and biosynthetic elucidation of ovoselenol, a selenium-containing antioxidant found in marine microorganisms.

The authors demonstrate that targeted protein degradation of the dengue virus capsid suppresses infection through capsid-dependent pathways rather than classical inhibition, revealing a new antiviral strategy effective against resistant viral variants.

The deactivation of CO₂ reduction electrocatalyst in microbial media remains a key barrier for hybrid bio-electrochemical systems. Here, the authors present a bioadaptive nickel single atom catalyst that resists organic poisoning to enable high-rate CO-mediated isopropanol production from CO₂.

H₂O, a primary proton donor, governs CO₂ reduction pathways and regulates selectivity, yet its coordination effects remain elusive. By exploiting the long-range structural order and porosity of crystalline coordination frameworks, this work uncovers how coordinated H₂O influences CO₂ reduction.

Bioactivity benchmarks are key to evaluating and improving methods to predict chemicals’ specific biological activity. Here, the authors find existing benchmarks poorly suit this goal; their assays are often well-predicted simply by counting cells. They propose new guidelines and curated benchmarks.

HTLV-1 type-C causes more severe disease than type-A, but the underlying reason is unclear. Here the authors show in a macaque model how type-C orf-I affects lung pathogenesis and the immune response to HTLV-1, providing a model to test viral targets for disease prevention.

Proteins assume complex 3D shapes even faster than does DNA, which is a simpler molecule.

Alkynes found in natural products are typically assembled by metal-dependent enzymes. The enzyme BesB instead forms a terminal alkyne-containing amino acid using pyridoxal phosphate as a cofactor. Here, the authors use structural and mechanistic investigations to identify the key features of BesB that allow it to carry out its fascinating chemistry.

EGFR inhibitors are standard of care in patients with EGFR-mutant non-small cell lung cancer (NSCLC) but resistance often develops. Here the authors report that the evolution of EGFR inhibitor resistance in EGFR-mutant NSCLC results in a sensitivity to the compound, MCB-613, and investigate the underlying mechanism of action.

The ferroptosis suppressor protein FSP1 has a critical role in ferroptosis protection of tumours across multiple in vivo models and is linked to worse prognosis in human lung adenocarcinoma, suggesting its potential as a therapeutic target in lung cancer.

The BAM complex is assisted by periplasmic chaperones, such as SurA, in its folding and insertion of proteins into the bacterial outer membrane. Here, the authors use disulphide bond engineering to trap transient protein complexes and solve their cryoEM structures to shed light on the cycle of SurA arrival, OMP delivery, and handover to BAM.

Engineering polymerases to synthesize alternative genetic polymers remains a challenging problem in synthetic biology. The current study offers insights into the structural and biochemical changes responsible for improving the fidelity and catalytic activity of a laboratory evolved TNA polymerase.

 A method for topological automatic cell type classification across subcellular resolution spatial transcriptomic platforms is proposed, resolving cell type information and locating sparsely dispersed cells in human kidney and mouse kidney and brain.

Here, Parzych et al describe the development of a DNA-delivered SARS-CoV-2 mAb cocktail displaying synergistic RBD binding that confers broad neutralizing activity against variants of concern and prophylactic efficacy in multiple small animal models.

An in-depth analysis of tissue biopsies from patients with multiple myeloma and CAR T cell therapy-associated immune-related adverse events (CirAEs) after treatment with commercial BCMA-targeted CAR T cell therapy shows that CD4⁺ CAR T cells mediate off-tumor toxicities and that high CD4:CD8 ratio at apheresis, robust early CAR T cell expansion, ICANS and ciltacabtagene autoleuce treatment are independently associated with the development of CirAEs.

The extent to which human bacterial pathogens broadly utilize ergothioneine as an antioxidant is unknown. Here, authors describe the discovery of a specific transporter for ergothioneine in a respiratory pathogen that is highly conserved among Firmicutes.

Engineered polyketide synthases historically have little to no activity. Here, the authors use updated modules from the pikromycin synthase to make 155 synthases, showing that the updated module has a higher success rate, but that ketosynthase gatekeeping and module skipping can prevent function.

CDK4/6 inhibitors are promising treatments for ER+ breast cancer, however resistance remains a challenge. Here, the authors analyse the NeoPalANA cohort and indicate that a 33 gene signature was predictive of response to neoadjuvant anastrozole and palbociclib.

Results of an early-phase breast cancer prevention trial demonstrate the potential for breast cancer prevention in premenopausal women with anti-progestin therapy by inducing epithelial–stromal remodelling and suppression of luminal progenitors.

Protein citrullination regulates the physiological function of proteins and is linked to various autoimmune disorders. Here, the authors report on the allosteric targeting of PAD1-4 leading to broad inhibition of protein citrullination in neutrophils.

Current proteolysis-targeting chimeras can promote the ubiquitination and subsequent degradation of both target and off-target proteins by inducing their respective proximity with the cereblon ubiquitin ligase. Now, by developing and deploying an off-target profiling platform, ‘bumped proteolysis-targeting chimeras’ can maintain on-target degradation efficacy with reduced off-targets.

Using structural, biochemical, and functional assays, the authors demonstrate that the E3 ligase KLHDC2, via newly developed small-molecule ligands, can be co-opted to target critical targets for degradation.

An einsteinium coordination complex is synthesized and spectroscopically characterized using less than 200 nanograms of einsteinium, enabling examination of its structure and measurement of an einsteinium bond distance.

Mucosal administration of a multivalent, adjuvanted vaccine against Clostridioides difficile promoted bacterial clearance and protected against morbidity, mortality, tissue damage and recurrence in mice.

Researchers studied the blood-based metabolome of over 23,000 people from ten ethnically diverse cohorts. They identified 235 metabolites associated with future risk of type 2 diabetes (T2D). By integrating genetic and modifiable lifestyle factors, their findings provide insights into T2D mechanisms and could improve risk prediction and inform precision prevention.

Understanding how materials respond to impacts at extreme strain rates is crucial, yet current approaches present significant challenges. Here, the authors report the use of a mechanophore-functionalized block copolymer to encode and report energy dissipation mechanisms in response to impacts.

Spin-polarized defects in 2D materials are attracting attention for future quantum technology applications, but their controlled fabrication is still challenging. Here, the authors report the creation and characterization of effective spin 1/2 defects via the atomically-precise generation of magnetic carbon radical ions in 2D WS₂.

Structural studies of the itch receptors MRGPRX2 and MRGPRX4 in complex with endogenous and synthetic ligands provide a basis for the development of therapeutic compounds for pain, itch and mast cell-mediated hypersensitivity.

Biochemical and structural analysis, combined with metadynamics simulations, illustrate how a single amino acid substitution switches a β-glycosidase from a double S_N2 mechanism to a front-face S_Ni-like mechanism.

How the necroptosis executioner, MLKL, converts to a killer form has been mysterious. Here, authors show RIPK3-mediated phosphorylation of human MLKL is the cue for pseudokinase domain dimerization before assembly of pro-necroptotic MLKL tetramers.