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Screening for substrate preference of the SARS-CoV and SARS-CoV-2 main protease Mpro leads to the development of activity-based probes useful for structural analysis and for visualization of active Mpro in infected patient epithelial cells.
A screening approach finds VH-domain antibodies that bind the SARS-CoV-2 Spike protein receptor-binding domain at its interface with host ACE2. Bi-paratopic and multivalent binders have high affinity and potency.
The plant cuticle was initially thought to act as a passive diffusion barrier. Genetic and metabolic analysis reveals that it is also a sink/concentrator for volatiles protecting cells from toxic effects of these hydrophobic compounds.
This Review summarizes the chemical and physical properties of methylated nucleobases in DNA and RNA, proposes a chemical classification of methylation types, and discusses recent advance in demethylation reactions mediated by dioxygenases.
Increased production of (S)-reticuline and other alkaloids is achieved through alleviating norcoclaurine synthase toxicity by targeting the enzyme to the peroxisome plus enlarging peroxisomes by expression of engineered transcription factors.
A family of riboswitches named Sensei that specifically sense iron has been discovered and characterized, which enables the authors to engineer metal ion sensing riboswitches to convert their metal selectivity.
A chemical glycobiology approach reveals that heparan-sulfate glycosaminoglycans regulate vascular development through direct interactions with angiopoietin (Ang) ligands and the Tie1 receptor of the Ang–Tie signaling system.
Structural analysis of transcription activation complex comprising E. coli transcription factor CueR, RNAP holoenzyme and promoter DNA reveals that CueR distorts the DNA conformation to promote the association of promoter with polymerase.
The whitefly Bemisia tabaci defends against plant glucosinolate toxins by serial addition of glucose moieties catalyzed by a pair of glycoside hydrolases, preventing toxin activation during feeding on the plant tissue.
A fluorescence-based sensor of PKA activity has increased brightness, dynamic range and signal-to-noise ratio over related sensors and is useful for visualizing kinase activity in HeLa cells, primary neurons and the cortex of awake mice.
Native ion mobility mass spectrometry reveals two isoforms of the two-pore domain K+ channel K2P4.1 have distinct binding preferences for lipids and show a relationship between the strength of individual lipid binding events and channel activity.
A bifunctional AURORA-A degrader induces the fast and specific degradation of this kinase in cancer cell lines, which enables targeting of non-catalytic, oncogenic functions of AURORA-A resulting in S-phase arrest and rampant apoptosis.
Immunomodulatory drugs are used for the treatment of multiple myeloma. ARID2, a component of the PBAF chromatin-remodeling complex, is a new pomalidomide-induced neosubstrate of CRL4CRBN, which accounts for its superior efficacy over lenalidomide.
Imaging of phosphatidylcholine, sphingomyelin and their interorganelle lipid transport in live cells, using azido-choline and a spatially limited bioorthogonal tag, suggests that autophagosomal membranes originate from the ER.
Virulence factors from various bacterial pathogens catalyze post-translational modification of key host proteins, including phosphate β-elimination and phosphoribosyl-linked ubiquitination, to suppress host immune defenses and promote infection.
Changes in O-GlcNAc levels controlled the actin contraction of fibroblasts in response to sphingosine-1-phosphate (S1P). Specifically, O-GlcNAc modification of the phosphatase MYPT1 maintains its activity to block S1P signaling.
Cryo-EM structural work shows sterols binding at four adjacent locations within the class F GPCR Smoothened (SMO), where the transmembrane core functions as a sterol tunnel in which occupancy activates SMO for downstream Hedgehog signaling.
Incorporation of the non-canonical amino acid 3-aminotyrosine into the chromophores of green fluorescent protein-based biosensors systematically red-shifts their fluorescent properties while maintaining brightness, dynamic range and responsiveness.
Pyruvate-responsive circuits based on an orthologous transcription factor and adaptation of an antisense transcriptional circuit were developed to sense pyruvate in Bacillus subtilis and redirect metabolism for optimized glucaric acid production.
Reengineering of the lac operon in E. coli from a ligand-inducible to a blue-light-regulated gene expression system facilitates optogenetic control of biotechnological applications including metabolic engineering and protein expression.
An irreversible small-molecule inhibitor of histone methyltransferase NSD1 is developed, which binds covalently to the C2062 residue in the catalytic SET domain and represses H3K36 dimethylation and target gene expression in leukemia cells.
Structural and biochemical analysis of E. coli transketolase with 2′-methoxy-thiamine shows that this antivitamin selectively inhibits the bacterial enzyme via a steric clash with a critical glutamate residue, preventing cofactor activation.
A cell-free system for cannabinoid production uses only low-cost inputs with 12 enzymes and can operate either aerobically or anaerobically, in addition to reducing ATP requirements by use of an engineered system for malonate-CoA biosynthesis.
Cryo-EM structural work defines binding of the insecticide CHL in the pseudo-voltage-sensor domain of ryanodine receptor RyR that triggers conformational changes leading to channel opening and explains the resistance to CHL by some insects.
A chemical screen targeting major epigenetic pathways identifies permissive epigenetic states that enable reprogramming with a broad range of transcriptional regulators and almost all octamer-binding (OCT) family members.
Structural and biophysical approaches suggest that structural preorganization is important for triggering endogenous CD8+ T cells and escape from immune tolerance, as demonstrated by a single nonsynonymous mutation in an ovarian cancer neoepitope
Application of an electrical field to Geobacter sulfurreducens biofilms stimulates production of OmcZ nanowires, which undergo a pH-induced conformational switch that causes increased stiffness and conductivity due to enhanced heme group π-stacking.
An αHER2 antibody–neuraminidase conjugate, which selectively targets the removal of sialic acids from glycans on breast cancer cells, bypasses a glycoimmune checkpoint and enhances tumor cell killing by the host immune system.
A PROTAC termed P4B targeting BRAF V600E mutant has been developed, which displays enhanced inhibitory function in cell lines carrying BRAF mutations that impart resistance to conventional BRAF inhibitors.
Genetic screens reveal a compendium of metabolic modifiers of lipid peroxidation. Tetrahydrobiopterin is essential under GPX4 inhibition, acting as a radical-trapping antioxidant that inhibits lipid peroxidation and is regenerated by DHFR.
The fluorescent chemogenetic reporters greenFAST and redFAST were engineered by protein engineering. They display orthogonal fluorogen recognition and spectral properties allowing efficient multicolor imaging of proteins in live cells and organisms.
The combination of heavy isotope labeling and ultra-high-pressure liquid chromatography coupled to triple-quadrupole mass spectrometry (UHPLC–MS) is used to quantify modified genomic cytosines in pluripotent stem cells in different states and reveals active turnover of methylcytidine in oxidation-dependent and oxidation-independent manners.
Levels of the endogenous bile acid cholic acid-7-sulfate (CA7S) increase in the gastrointestinal tract of both mice and humans after sleeve gastrectomy. CA7S acts through the G-protein-coupled receptor TGR5 to increase glucose tolerance during insulin resistance.
Chemical profiling in hyponeddylated cells coupled with multi-omics target deconvolution led to the identification of molecular glue degraders of cyclin K that function by inducing proximity between the CRL adaptor DDB1 and a CDK12–cyclin K complex.
The structural analysis of a covalent E2–E3 ubiquitin transfer intermediate reveals the ubiquitin relay mechanism via two Cys residues of E3 ligase MYCBP2, which is related to neurite growth and neurite protection phenotypes.
An orthogonal O-glycan biosynthesis system was engineered in Escherichia coli to support the production of glycoproteins displaying human mucin O-glycans, including Tn antigens, in living bacteria and in cell-free extracts.
TAp63α monitors the genome integrity in oocytes. After DNA damage, TAp63α is activated, involving multiple phosphorylation steps by CK1 with different kinetics due to an unusual CK1/TAp63α interaction in which the product of one step inhibits the next.
Biocatalytic cascade reactions using engineered variants of ferulic acid decarboxylase coupled to carboxylic acid reductase utilize carbon dioxide fixation to enable the carboxylation and functionalization of styrene and other aromatic compounds.
A robust mass spectrometry workflow was developed for rapid drug perturbation profiling in multiple cell lines, enabling improved mechanistic deconvolution of single compounds and revealing novel mechanisms of action.
Highly selective activators of IRE1/XBP1 splicing pathway were identified via high-throughput screen, which promoted the degradation of APP and reduced APP-associated mitochondrial toxicity in an IRE1-dependent manner.