Hypusination is a two-step enzyme-mediated post-translational modification that converts lysine into hypusine. The modification is unique to the eukaryotic translation factor eIF5A, which is essential for overcoming ribosome stalling in polyproline regions. Dysregulation of hypusination is implicated in cancer, diabetes and hypusination-related neurodegeneration, including the recently identified neurodevelopmental

Cell-type-specific delivery of therapeutics requires selectivity to prevent delivery to off-target cells. However, developing methods that provide the desired selectivity remains challenging. Toxins such as anthrax, botulinum and diphtheria toxin have been explored as delivery systems due to their ability to undergo endocytosis through interactions with cells via the toxin receptor-binding domain and

Original reference: Mol. Cell 83, 1725–1742.e12 (2023)

Enzymes have many highly desirable properties as catalysts, but adapting them to non-natural reactions or conditions requires re-design and optimization. One approach is directed evolution, which does not require prior knowledge of the structure or enzyme dynamics but takes many rounds to generate catalysts with the desired attributes or reactivity. Continuous evolution of enzymes in a high-throughput

Methicillin-resistant Staphylococcus aureus (MRSA) is a well-known superbug that has the staphylococcal cassette chromosome mec, a mobile genetic element containing genes that enable resistance to β-lactam antibiotics. Specifically, the mecA gene encodes the penicillin-binding protein PBP2a involved in peptidoglycan biosynthesis, cell-wall formation and resistance to antibiotics. MRSA can be categorized

Probiotic bacterial strains such as Escherichia coli Nissle are potentially useful for the targeted delivery of therapeutic molecules to disease sites. However, current strategies for ensuring that these Gram-negative strains deliver their cargo are mostly limited to programmed lysis or display on the outer surface of the bacteria. To promote the release of therapeutic proteins from E. coli Nissle

Australia is home to the stinging nettle tree (Dendrocnide excelsa), which is full of excelsatoxin (ExTxA), a peptide structurally reminiscent of spider and cone-snail venoms known to target voltage-gated sodium channels (NaV). The leaves of this plant are covered in dense, toxin-laden trichomes that can cause excruciating pain that lasts for weeks.

Now, using cryo-electron microscopy, Hu et al. have determined the structure of FKS1 from Saccharomyces cerevisiae. FKS1 consists of a wedge-shaped transmembrane (TM) domain of 17 helices, cytoplasmic GT and accessory (AC) domains, and several unstructured extracellular loops. The TM domain contains multiple bound lipids that probably contribute to stabilization, as well as a pair of pockets, one each

Original reference: Science 379, 996–1003 (2023)

TDP-43 is an RNA-binding protein that forms toxic aggregates in the neuronal cytoplasm that are commonly detected in multiple neurodegenerative diseases. Mislocalization of TDP-43 to the cytoplasm is thought to disrupt RNA processing, which may also contribute to its pathological effects. Loss of nuclear TDP-43 causes alternative splicing of the gene STMN2, which encodes stathmin-2, a key protein that

Fabricating site-specific protein conjugates is important for the development of protein therapeutics and uniform constructs that can be used to study function. Chemical ligation is one way to modify proteins; another is to use peptide ligases — such as sortase A, or peptidyl asparaginyl ligases (PALs) — which offer the benefits of enzymatic catalysis. PALs have a much higher catalytic efficiency than

Original reference: Science 379, 717–723 (2023).

Antiviral cyclic nucleotides and oligonucleotides are utilized by various organisms for innate immune signaling; in humans, these molecules activate the STING-dependent interferon pathway, whereas bacteria utilize ancestral cGAS/DncV-like nucleotidyltransferases (CD-NTases) to fight bacteriophage infection. Although the molecular basis of eukaryotic innate immune signaling is known, details of its

Metabolites such as short-chain fatty acids can interact with chromatin and affect transcription by modifying histone proteins. The variety of histone modifications makes it technically hard to delineate their function in a site- and modification-type-specific way. Qin et al. developed a single-site-resolved multi-omics (SiTomics) strategy based on genetic code expansion technology to profile the interacting

Original reference: ACS Chem. Biol. 18, 595–604 (2023).

The leaves of the tree Mitragyna speciosa (also known as kratom) contain a complex mixture of monoterpene indole alkaloids, including one called mitragynine. Mitragynine has pain-relieving effects similar to those of opioid drugs, which has led to the use of kratom as a natural remedy for pain and the management of opioid dependence. However, the biosynthesis of mitragynine is not fully understood

NRF2 is a transcription factor that promotes the expression of genes encoding anti-oxidant molecules under conditions of high oxidative stress. NRF2 is normally restrained through interactions with KEAP1 under low stress, which promotes NRF2 degradation. Increased levels of NRF2 were thought to enable cancer cells and tumors to tolerate high levels of reactive oxygen species to survive and proliferate