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Glycosylation of Notch receptors regulates ligand-induced Notch signaling, which is essential for normal development in animals. Fucose analogs targeting Notch glycosylation serve as ligand-specific Notch inhibitors and facilitate the understanding of how O-glycan regulates Notch–ligand interactions.
Modification of folded proteins at will, within any sequence context, remains an elusive goal. A proteome-wide screening approach has now identified a set of protein ligases that enables conjugation of peptides to almost any protein N terminus, overcoming longstanding limitations in protein engineering.
Phage-assisted evolution can rapidly improve the efficiency and substrate specificity of orthogonal aminoacyl-tRNA synthetases. Furthermore, the crystal structure of the pyrrolysyl-tRNA synthetase N-terminal domain reveals the basis for these improvements and provides a structural rationale for orthogonality.
The 'off-targets' of a drug are often poorly characterized yet could be harnessed in the treatment of complex diseases. A recent study used a small-molecule screening in non-small-cell lung cancer to repurpose an FDA-approved ALK/IGF1R inhibitor and uncover its mechanism of action.
A potent and selective inhibitor of protein SUMOylation, a ubiquitin-like post-translational modification, has been developed, shedding light on the potential for developing new classes of anticancer therapeutics.
Structure-based computational methods have contributed to recent successes in the development of small molecules to study GPCR function and to act as therapeutics, including the identification of new ligands for orphan GPCRs, allosteric regulators, and biased ligands.
In contrast to proteins, no intrinsically fluorescent RNA is known to exist in nature. In this issue, a new, red-shifted aptamer–fluorophore complex for RNA imaging that has enhanced photostability is described. The crystal structure of this complex reveals a novel form of RNA small-molecule recognition.
Genome mining reveals a new ribosomally synthesized and post-translationally modified peptide (RiPP) from Klebsiella pneumoniae. This new antibiotic inhibits bacterial ribosomes by obstructing the peptide exit tunnel, and its modular nature presents a unique opportunity for future engineering of antibacterial drugs.
The introduction of a cyclopropyl group is critical for imparting colibactin with the ability to cleave DNA. Nonribosomal peptide synthetase ClbH and polyketide synthase ClbI are now shown to work in concert to convert S-adenosylmethionine into this cyclopropyl group.
The ability to solubilize membrane proteins while retaining their native function is a persistent challenge. Re-engineering of the membrane protein DsbB into a soluble cytoplasmic version maintained its activity and enabled recompartmentalization of the periplasmic DsbAB disulfide bond–forming system.
Extracellular vesicles (EVs) are a class of secreted membrane particles capable of transferring biological molecules between cells. Metabolomics measurements indicate that isolated EVs also have autonomous metabolic enzyme activities, including the unexpected identification of endogenous human asparaginase activity.
An allosteric inhibitor of Mycobacterium tuberculosis tryptophan synthase—an enzyme that is nonessential for in vitro growth—has potent antimicrobial activity, revealing a potentially expanded target list for antimicrobials and greater chemical space for new inhibitors.
Allosteric modulation and biased agonism at GPCRs could be manifestations of the same underlying 'conformational selection' mechanism, and these can be harmonized by considering the influence of ligand–receptor residence time and kinetic context.
Kinetochores form the critical interface with spindle microtubules that accounts for chromosome movement and segregation fidelity during mitosis. Spatial and temporal control of motor protein and checkpoint signaling at kinetochores is now possible with a new set of optogenetic tools.
The genome of the poisonous mushroom Omphalotus olearius provides a potent new biocatalytic strategy for installing backbone N-methyl amides on ribosomally synthesized peptides. This discovery could yield new biotechnologies for drug development from peptide macrocycles.
Peroxidases, rather than simply reducing H2O2 to water, also convey oxidation signals to proteins such as transcription factors. A new study reveals how a scaffold protein enables formation of a mixed disulfide between the peroxidase and a transcription factor.
New structures of the glucagon-like peptide-1 (GLP-1) and glucagon receptors in complex with peptide and nonpeptide ligands provide a comprehensive, detailed picture of the molecular mechanisms of action of family B GPCRs. This opens the door for true structure-based drug discovery aimed at both novel orthosteric and allosteric subsites of the receptors.
The organelles and subcellular compartments of yeast provide distinct environments and physical separation from the cytosol, enabling opportunities to target biosynthetic pathways to these compartments and enhance production of desirable compounds.
Lipid II embodies the bricks used to build the essential bacterial cell wall component peptidoglycan. A facile new procedure for preparation of species-specific Lipid II in high yields can now be used to unlock the door to antibiotic discovery.
A variety of chemical and enzymatic techniques, each with their own considerations for use, have been developed for the site-selective bioconjugation of desirable moieties to proteins via the unique handle of the N terminus.
