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The spliceosome is an immensely complex molecular machine tasked with stitching together coding regions of genes. New work reveals how a small molecule can affect this machinery in a model of spinal muscular atrophy, a disease linked to aberrant splicing.
The molecular basis of biomaterial assembly and function can provide inspiration for new materials science designs. New research explains the squid beak's transition from soft to hard through the identification of two new families of proteins with unusual physical properties.
A modified amphotericin antifungal that is less toxic to human cells, owing to its increased preference for its fungal ergosterol target versus human cholesterol, can still evade the evolution of resistance.
The ability to vary a drug's residence time on a target is important for drug optimization. A series of reversible covalent inhibitors of select kinases demonstrates the feasibility of tuning residence time from minutes to days through modification of noncovalent features of the molecules.
Biosensors are emerging as an important tool to evolutionarily engineer metabolic pathway enzymes for the microbial production of chemicals. A colorimetric biosensor used to increase dopamine levels in yeast now enables the production of benzylisoquinoline alkaloids from glucose.
One-carbon metabolic pathways create new opportunities for metabolic engineering, but natural pathways have limitations in catalytic efficiency and interspecies transferability. Now a computationally designed enzyme, formolase, enables the construction of a synthetic metabolic pathway in Escherichia coli for assimilation of formate into a glycolytic intermediate in only five reaction steps.
Binding kinetics (BK) has an indispensable role in pharmacodynamics (PD). Incorporating slow BK into a mechanistic PD model is shown to have predictive value for in vitro cellular and in vivo animal antibacterial efficacy.
Single-step site-specific labeling of native proteins is one of the holy grails in the chemical biology field. 2-Pyridinecarboxyaldehyde derivatives are shown to react selectively at the N terminus of proteins to form stable conjugates, irrespective of the nature of the N-terminal amino acid, enabling the straightforward introduction of useful functional groups into a wide array of proteins.
Heterodimerization of G protein–coupled receptors can lead to the activation of intracellular pathways that are not triggered by either of the individual receptors. This property may lead to the development of new therapeutic approaches showcasing increased efficiency and selectivity.
The demonstration of excitation energy dissipation via energy transfer in a cyanobacterial chlorophyll-carotenoid membrane complex provides evidence that this mechanism may also operate in the light-harvesting complex antennae of higher plants.
Bacterial translation elongation factor P (EF-P) is essential to overcome ribosome stalling at polyproline stretches during protein synthesis. A new mechanism of EF-P activation, identified in a subset of Bacteria, involves addition of the sugar L-rhamnose to a critical arginine residue.
Cytosolic proteins can be modified cotranslationally by the installation of O-GlcNAc groups onto serine and threonine residues. This modification suppresses cotranslational ubiquitination and stabilizes proteins against proteasomal degradation.
Although resveratrol is thought to provide many beneficial health effects, its cellular targets and mechanism of function are still under investigation. A new study found that resveratrol binds to tyrosyl transfer-RNA synthetase, resulting in the activation of the stress response effector PARP1.
The physical arrangement of enzymes within native metabolic pathways is emerging as an important but underexplored area of molecular biology. Recent advances in mass spectrometry enabled confirmation of the proposal that the Krebs cycle enzymes form a complex and suggest that substrate channeling is the most likely benefit to this structural arrangement.
Microbial natural products and the specific subset with antibiotic activity, 'the antibiotic'ome', consist of a dizzying array of structures and exert their effects by many known modes of action. In this issue, Cociancich et al. describe a unique natural product that—along with a compound identified in a recent publication by Baumann et al.—defines a new antibacterial chemical scaffold that acts on a rarely hit target, DNA gyrase subunit A.
Aggregation of α-synuclein (αSN) is critical to the development of Parkinson's disease (PD), but the role of membranes in this process has been unclear and controversial. Galvagnion et al. demonstrate and model how lipids can stimulate αSN aggregation over a narrow range of lipid:protein stoichiometries.
The reliable identification of microRNA (miRNA) targets remains an elusive goal. A new technique, using specially modified synthetic miRNAs to directly capture bound RNAs, brings us closer.
Lysophosphatidylserines (lyso-PSs) are an emerging class of signaling lipids implicated in human inflammatory and autoimmune diseases. A newly discovered phosphatidylserine-specific lipase, ABHD16A, together with the recently described lyso-PS lipase ABHD12 shed light on the in vivo regulation of lyso-PS, providing a potential enzymatic target for modulating neuroinflammatory responses.
Recent studies on two enzyme classes operating at the membrane interface showcase an unanticipated degree of structural plasticity involving domain swapping and marked secondary structure reshuffling. This structural variability in topology is key to functional diversification and catalytic prowess.
