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The authors develop a ribozyme, Tx2.1, that is capable of aminoacylating tRNA with specificity for the anticodon from directed evolution of a T-box riboswitch. Tx2.1 could be used to charge non-natural amino acids in an in vitro translation system.
d-Cycloserine inactivates alanine racemase by forming an adduct with the pyridoxal 5′-phosphate cofactor, but structural and spectroscopic analyses reveal that reactivation occurs on adduct hydrolysis and product rearrangement to a stable oxime.
A structural study of one of two human phospholipase D enzymes, hPLD1, helps define the determinants of substrate recognition, the highly regulated enzymatic activity, as well as activation by PIP2 and RhoA.
A cryo-EM structure of potato virus X shows that virions are formed by repeats of segments of coat protein protomers arranged in a left-handed helical structure and reveals details of the RNA–capsid interactions, which shed light on virus assembly.
A cryo-EM structure of the GPCR α2B adrenergic receptor (α2BAR) in complex with the selective agonist dexmedetomidine and the G protein Go suggests a mechanism of selective activation and provides insights into G-protein coupling activity.
Engineering of a synthetic circuit that couples transcriptional and protein turnover regulation to a fluorescent protein readout enables sensitive monitoring and amplification of gene expression signals from the unfolded protein response pathway.
Deep mutational scanning reveals that α-synuclein adopts a membrane-bound α-helix conformation with increasing dynamics towards the C terminus. This helical conformation is associated with its cytotoxicity.
A set of CRISPR–Cas9-based genetic screens in a haploid human cell line identifies more than 200 gene–drug associations involving solute carriers (SLCs), transporters important for the uptake and activity of cytotoxic drugs.
A small-molecule ligand of the APC/C activator Cdc20, which prolongs mitosis in unperturbed cells, instead shortens mitosis when the spindle checkpoint is activated, producing an opposite effect in a different regulatory context.
A pair of fluorescent DNA-based probes for nitric oxide reveals that nitric oxide synthase 3 activity in the trans-Golgi network is essential for Golgi structural integrity, despite being tenfold less active there than at the plasma membrane.
Small-molecule inhibitors of HIV-1 membrane fusion and infectivity act by partially inserting into a hydrophobic binding pocket formed by the membrane-proximal external region of Env spikes, blocking conformational changes of Env required for fusion.
Structural characterization of WbbM, an enzyme involved in O2a-antigen biosynthesis in Klebsiella pneumoniae, reveals two unique active sites with galactopyranosyl- or galactofuranosyl-transferase activities for oligosaccharide polymerization.
Tuning CRISPR–Cas9 nuclease specificity enables precision genome engineering. Identifying arginine residues along the bridge helix of SpCas9 that mediate Cas9 mismatch sensitivity enabled engineering of Cas9 with increased specificity in human cells.
HIDE probes were developed for long time-lapse imaging of endolysosomes and their dynamics at super-resolution. These probes enabled analyses of endosome motility in primary fibroblasts from patients with Niemann–Pick C with distinct mutations in NPC1.
A high-throughput small-molecule drug screening platform enabled the detection of compounds targeting the functional interactions of receptor tyrosine kinases and identifies four new EGFR triple-mutant inhibitors.
Use of receptor variants in knock-in mice to dissect phosphorylation-dependent signaling from G protein-dependent signaling mediated by acetylcholine receptor M1 mAChR defines the ability of receptor ligands to modulate anxiety and locomotion behaviors.
In place of the expected flavin-C4a-(hydro)peroxide intermediate, certain flavin monooxygenases such as RutA instead use a flavin-N5-peroxide intermediate as a catalytic nucleophile, enabling chemistry not accessible to canonical monooxygenases.
The ER exit site component Sec16A was identified as the target of Retro-2, a small-molecule inhibitor of protein toxins and pathogens. Retro-2 treatment alters retrograde early/maturing endosomes-to-Golgi trafficking of Shiga toxin.
Susceptibility to ferroptosis can be modulated by nitric oxide (NO•) and NO synthase iNOS and through enrichment of activated M1 macrophages. NO inhibits the lipoxygenase 15-LOX that drives production of pro-ferroptotic lipids in macrophages.
Using genome-wide CRISPR–Cas9-mediated suppressor screens, cytochrome P450 oxidoreductase was identified as a contributor to ferroptotic cell death by promoting phospholipid peroxidation in various cellular lineages.
Patrick et al. used single-molecule optical tweezers to study the enzymatic activity and dynamics of product release of telomerase and provide direct evidence for the presence of an anchor site in elongating telomerase.
Redesigning the central carbon metabolism of Escherichia coli with the reductive glycine pathway enables growth on the one-carbon compounds formate and CO2, and the addition of methanol dehydrogenase further enables growth on methanol and CO2.
Certain cyanobacteria use an alternative biotin biosynthetic pathway that replaces BioA with the dehydrogenase BioU, a suicide enzyme that catalyzes its reaction via conjugation to Lys124 and loses the amino group of this residue in the process.
A covalent pan-inhibitor of bacterial bile salt hydrolases developed by adding a chenodeoxycholic acid moiety to the warhead is not bactericidal and is therefore useful for studying the effects of bile acids on host physiology.
Crystal structures of phospholipase hPLD1 and hPLD2 catalytic domains and an analysis of the binding modes of dual and isoform-selective inhibitors define mechanisms of PLD regulation and catalytic activity.
NMR structural analysis of an active state of the β2-adrenergic receptor defines a unique orientation for the intracellular half of TM6, responsible for G-protein binding, including an equilibrium among three conformations of a key microswitch.
X-ray crystallography, solution NMR and biochemical and cell-based analyses reveal a model where catalytically repressed receptor tyrosine kinases accomplish activation loop (A-loop) tyrosine transphosphorylation.
A series of positive allosteric modulators of NMDA receptors that can increase agonist potency, increase channel-open probability, and slow receptor deactivation can also decrease single-channel conductance and decrease calcium permeability.
Lasonolide A is hydrolyzed into a cytotoxic metabolite by a lipid droplet-associated orphan serine hydrolase, showing that lipid droplets can promote drug toxicity by both accumulating and metabolizing drugs in cells.
The X325 protein family is highly similar to lytic polysaccharide monooxygenases (LPMOs) in regulation, structure and copper coordination by a histidine brace, yet lacks LPMO activity and suggests the evolution of an alternative function in fungi.
A chemoproteomics and protein engineering strategy to investigate metabolic activity of lipid kinases led to assignment of a key role for atypical C1 domains in directing fatty acyl specificity of diacylglycerol kinase function in live cells.
Polypeptide GalNAc-transferase T3 catalyzes the specific glycosylation of threonine-178 of fibroblast growth factor 23, and structural insights reveal a unique lectin-based mechanism of substrate recognition.
In cotton, a specialized glyoxalase I variant, SPG, has lost its glutathione-binding sites and organelle-targeting signal during its evolution to catalyze the aromatization of cyclic sesquiterpenes as part of the gossypol biosynthetic pathway.
In the fungal pathogen Cryptococcus neoformans, Bim1 is a copper-binding lytic polysaccharide monooxygenase-like protein that participates in copper uptake in concert with the Ctr1 importer to drive virulence mechanisms during fungal meningitis.
Designed heterotrimers of collagen I, locked in three possible chain registers, enable structural and functional characterization of each permutation, leading to identification of the AAB heterotrimer as the most active and therefore likely to occur biologically.
A set of orthogonal coiled-coil peptide heterodimers were developed to enable control of protein localization as well as transcriptional regulation by enhancing effector recruitment to TALE and CRISPR–dCas9 systems in mammalian cells and in vivo.
The authors utilize fluorescence-activated cell sorting coupled with next-generation sequencing, as well as dynamic modeling, to study the molecular mechanism underlying indole signaling and reveal different roles of the two ends of tnaC in coordinating transcription and translation.
UBE2T adopts an allosteric activation mechanism to mediate site-specific ubiquitination of Fanconi anemia complex. Interaction with FANCL induces a cascade of conformational changes of UBE2T and leads to exposure of substrate-binding sites.
Single-molecule FRET technologies reveal the mechanism of sequence-specific translational inhibition induced by two antibiotics, chloramphenicol and linezolid, where aminoacyl-tRNA was repeatedly rejected from the A-site and failed to form a peptide bond.
Bacterial two-component signaling machinery has been reprogrammed for orthogonal signaling in mammalian cells that is triggered by small-molecule-mediated dimerization or ligand-induced GPCR/β-arrestin signaling.
A combinatorial engineering strategy encompassing pathway regulation, heterologous enzymes and subcellular trafficking enables repurposing of the phospholipid biosynthetic pathway in Saccharomyces cerevisiae for the production of oleoylethanolamide.
An improved workflow combining de novo transcriptome assembly and Ribo-seq validated by cellular antigen display is developed to maximize small peptide discovery, leading to identification of thousands of unannotated protein-coding smORFs.
A photocrosslinking-based nucleosome profiling approach is used to identify a conserved basic motif in the ISWI remodeler SNF2h that anchors it to the acidic patch of nucleosome and enables nucleosome sliding activity.
PUS10 exhibits two different functions: one is to promote miRNA biogenesis in a catalytically independent manner; the other is to install pseudouridine modification in tRNAs in a catalytically dependent manner.
The crystal and cryo-electron microscopy structure analysis of the DCAF15–DDB1–DDA1–indisulam–RBM39 complex revealed the detailed mechanism of action of indisulam-induced RBM39 degradation and defined an α-helical degron motif in RBM39.
The RNA endonuclease CPSF3 was identified as the cellular efficacy target of the small molecule JTE-607, revealing pre-mRNA processing as a vulnerability in cancers such as Ewing’s sarcoma that are characterized by aberrant transcription.
Single-particle tracking and mathematical modeling methods reveal the searching mechanism of CTCF for its cognate sites on DNA. An RNA-binding region in CTCF mediates its trapping in small zones and increases its target search efficiency.
A computational approach for designing GPCRs with new signaling functions including allosteric signaling properties yielded D2 receptor variants with predictable G-protein signaling responses, some with enhanced potency and responses to dopamine.