Research articles

The systematic exploration of off-patent drugs in combination with the antibiotic minocycline uncovers unexpected synergies in antibiotic-nonantibiotic pairs. These interactions are exemplified by the nonantibiotic loperamide, which finds a new function in facilitating tetracycline uptake.

The toxin-antitoxin pair MqsR and MqsA are linked to biofilm formation, quorum sensing and motility, but their specific role in these and other cellular processes is unclear. The demonstration that MqsA directly represses transcription of rpoS, encoding the master regulator of the stress response, provides a unifying explanation.

A target-identification strategy based on the yeast three-hybrid system and the SNAP-tag labeling technique identifies new targets for three small-molecule drugs and helps identify a new mechanism for the activity of the anti-inflammatory drug sulfasalazine involving inhibition of sepiapterin reductase.

Heat causes oligomerization and targeting of the ER-based calcium sensor STIM1 to ER–plasma membrane junctions but prevents the functional coupling between STIM1 and the calcium-permeable Orai1 ion channel, resulting in a unique heat off-response of calcium entry.

A specific and potent inhibitor of the DNA damage response kinase ATR can exploit synthetic lethality between ATR and the related kinase ATM to sensitize ATM-defective cancer cells to ionizing radiation and DNA-damaging drugs.

Synthesis of new vancomycin-like glycopeptides offers opportunities to overcome antibiotic resistance. The crystallographic identification of a reaction intermediate close to the surface of a glycopeptide tailoring enzyme leads to a new biocatalytic strategy to create two classes of teicoplanin analogs.

Experiments on reconstituted liposomes and sperm capacitation, an activation process involving the reduction in membrane cholesterol content and subsequent exposure of surface carbohydrate, show that cholesterol masks the presentation of glycolipid head groups by inducing a conformational shift in the glycan moiety.

Cannabis-induced analgesia results from potentiation of the α1 and α3 glycine receptors via a specific interaction with a transmembrane segment of the receptors, and this distinguishes the analgesic effects from the psychoactive effects of cannabinoids.

A selective, short-acting agonist for the sphingosine-1-phosphate receptor S1P₁ and GFP-S1P₁ knock-in mouse model are used to show that both receptor degradation and receptor reserve underlie the mechanisms of lymphocyte sequestration by agonists.

Going against the classical model of β-arrestin–mediated internalization and downregulation of GPCRs, FRET, FRAP and time-lapse imaging show that PTHR remains active when bound to β-arrestin and is ultimately terminated by retromer complex, a complex involved in transport from endosomes to the Golgi.

Mutant p53 can attenuate the function of wild-type p53, p63 and p73. An aggregation-nucleating sequence in p53 that is revealed in structurally destabilized mutants can induce coaggregation with p63 and p73, resulting in their sequestration in cellular inclusions.

The ribosomal production of two short peptides conserved across divergent plant species unexpectedly uses an open reading frame for an unrelated protein, albumin, as well as albumin processing–machinery to create mature cyclic sequences.

Metabolic engineering often involves the addition of enzymes, redirection of metabolic flux or elimination of undesirable endpoints and thus requires laborious optimization of numerous parameters. A new method to derive 'blueprints' from real-time measurements of metabolic networks significantly accelerates this process as demonstrated with the production of dihydroxyacetone phosphate.

Magic-angle spinning ssNMR used to monitor the E. coli integral membrane protein DGK reconstituted into lipid bilayers reveals the kinetics and mechanisms of this enzyme in both the membrane phase where diacylglycerol is converted to PA and in the aqueous phase where ATP is converted to ADP.

A screen for compounds that alter fat content in C. elegans identifies a novel agonist of an AMP-activated kinase pathway that reduces fat storage as well as implicates the transcription factor K08F8.2 as a regulator of fat metabolism.

Hydrogenases can generate hydrogen gas, but oxygen sensitivity often limits their practical applications. Investigations of an oxygen-tolerant [NiFe] hydrogenase now show that an unusual FeS cluster with six cysteine ligands alters the electron pathway to reduce unwanted oxygen and maintain enzyme function.

A potent and selective inhibitor of the kinase LRRK2 identified using an in vitro ATP-site competition binding assay also inhibits the G2019S mutant, implicated in Parkinson's disease, as well as the regulatory feedback loop where LRRK2 is phosphorylated and binds 14-3-3 protein.

The use of synthetic analogs to explore substrate promiscuity during trehalose incorporation into the mycobacterial cell wall yields a fluorescent probe that can be used to examine M. tuberculosis cell biology and detect this harmful pathogen within macrophages.

As metabolic reactions are often in equilibrium, product sequestration is often used to drive engineered pathways forward. For n-butanol, however, this is not possible; instead, introducing kinetic barriers for backwards reactions significantly increases product yield.

NMR reveals the dynamic stretching ability of the subdomain LH of the intrinsically disordered p21, providing a physical basis for the binding and functional diversity in its cell cycle regulatory role as a modulator of Cdk–cyclin complexes.