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Development of a malolactone electrophile that contains sufficient ring strain to counteract the weak nucleophilicity of aspartate enables covalent targeting of K-Ras-G12D, which is commonly found in pancreatic cancers.

Chemically reactive metabolites such as formaldehyde are often toxic and are proposed to react promiscuously with biomolecules. New work shows that some reactive sites on proteins are uniquely sensitive to formaldehyde, leading to functionally important regulation of protein and cell functions.

A proteome-wide thermal profiling study of osmolyte action on E. coli and human proteins within the cellular milieu reveals mechanisms of protein thermal stabilization by osmolytes and in situ behavior of intrinsically disordered proteins.

Structural, functional and computational studies uncover the molecular details of antiviral drug recognition and membrane translocation by a concentrative nucleoside transporter.

This Review provides an overview of different RNA base editing technologies, including the RNA-targeting platforms and modification effectors, with a focus on the emerging programmable RNA base editors and their potential in correcting pathological mutations.

Adipose triglyceride lipase (ATGL), an enzyme in fatty acid metabolism, was identified as a negative regulator of the noncanonical inflammasome. ATGL binds to lipopolysaccharide and catalyzes the hydrolysis of fatty acid side chains blocking inflammasome activation.

A chemoproteomic method was developed that enables the global discovery of metal-binding proteins (MBPs) in proteomes, where the thermal stability of MBPs is perturbed by metal chelators. This tool, called METAL-TPP, is used to discover MBP candidates in the human proteome and provides a valuable method for functional annotation of MBPs in cell biology.

Developing inhibitors for SH2 domains is challenging due to their shallow pockets and highly charged ligands. Structure-guided drug design has enabled the discovery of a cell-permeable covalent inhibitor of the SOCS2 SH2 domain, a key regulator of cytokine signaling pathways.

O-linked N-acetylglucosamine (O-GlcNAc) is an endogenous form of glycosylation that alters the structure of α-synuclein amyloid fibrils and attenuates their pathogenetic properties. The modified fibrils have a significantly reduced ability to seed the aggregation of endogenous α-synuclein in cultured neurons and in mice brains in vivo, which results in reduced pathology.

NinaB is an isomerooxygenase that generates visual chromophore (11-cis-retinal) from carotenoid substrates. Here Solano et al. reveal the structural basis for NinaB isomerase activity, providing new insights into the evolution of visual chromophore synthesis by carotenoid cleavage enzymes.

BURP-domain proteins are an unexplored family of plant-specific, copper-dependent peptide cyclases. Here the authors show that a BURP-domain protein has a particular protein fold, investigate its mechanism and provide evidence for intramolecular modification in RiPP biosynthesis.

Zhou et al. developed a specific small-molecule inhibitor of astrocytic Kir4.1 channels, Lys05, which exerts rapid-onset antidepressant effects in rodents without unwanted side effects, indicating Kir4.1 as a promising drug target.

Nonribosomal peptide synthetases produce diverse natural products, including many valuable therapeutics. Although the condensation domains that catalyze peptide bond formation in these multifunctional enzymes have been difficult to engineer, a yeast display system that was developed to screen millions of variants now enables efficient reprogramming of synthetase substrate specificity.

Transporters and channels have strong potential as drug targets, but drug discovery targeting these membrane-embedded molecules is challenging. Fragment-based ligand discovery combined with chemical proteomics offers a promising solution to the search for inhibitors of solute transporter family members.

α-Synuclein and tau can form multiple amyloid structures or strains that are associated with different neurodegenerative diseases, suggesting a strain–toxicity relationship. Now, it has been shown that O-GlcNAc modification of α-synuclein results in the formation of an amyloid strain that is largely nonpathogenic in vivo, supporting structure-dependent toxicity and another protective role for O-GlcNAc.

Sulfated compounds produced collaboratively by the microbiome and the host have important biological functions. This Review highlights the production of select sulfated carbohydrates, amino acid derivatives and steroidal metabolites and discusses their influence on health. The Review also explore potential roles of sulfated molecules in disease detection, prevention and treatment.