In vivo chloride concentrations surge to proteotoxic levels during acid stress

October 15th, 2018 by Frederick Stull

In vivo chloride concentrations surge to proteotoxic levels during acid stress

In vivo chloride concentrations surge to proteotoxic levels during acid stress, Published online: 15 October 2018; doi:10.1038/s41589-018-0143-z

Protonation of periplasmic protein carboxylic groups creates a Donnan equilibrium in the bacterial periplasmic space at low pH, leading to accumulation of Cl− and unfolding and aggregation of periplasmic proteins, which can be rescued by chaperones.
  • Posted in Nat Chem Biol, Publications
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The splice is right

October 15th, 2018 by James Palacino

The splice is right

The splice is right, Published online: 15 October 2018; doi:10.1038/s41589-018-0147-8

Current drug discovery efforts focus on proteins because of their ability to form stable, structured pockets. A recent study demonstrates that targeting stable, structured bioactive RNA motifs, such as autocatalytic introns, may provide a novel method of expanding druggability and selectivity.

Small molecules that target group II introns are potent antifungal agents

October 15th, 2018 by Olga Fedorova

Small molecules that target group II introns are potent antifungal agents

Small molecules that target group II introns are potent antifungal agents, Published online: 15 October 2018; doi:10.1038/s41589-018-0142-0

High-throughput screening followed by an examination of structure–activity relationship-based optimization resulted in the identification of potent small-molecule inhibitors of group IIB intron splicing in fungal organisms.
  • Posted in Nat Chem Biol, Publications
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New tricks for an old drug

October 8th, 2018 by Barbara S. Nelson

New tricks for an old drug

New tricks for an old drug, Published online: 08 October 2018; doi:10.1038/s41589-018-0137-x

The prodrug dimethyloxalylglycine (DMOG) is a well-known tool compound used to study hypoxia. New findings reveal that DMOG also inhibits glutamine metabolism and can be exploited to selectively kill some cancer cells, highlighting important caveats when using DMOG for hypoxia studies.

MCT2 mediates concentration-dependent inhibition of glutamine metabolism by MOG

October 8th, 2018 by Louise Fets

MCT2 mediates concentration-dependent inhibition of glutamine metabolism by MOG

MCT2 mediates concentration-dependent inhibition of glutamine metabolism by MOG, Published online: 08 October 2018; doi:10.1038/s41589-018-0136-y

High intracellular concentrations of the α-ketoglutarate analog N-oxalylglycine, owing to MCT2-mediated transport of its newly described prodrug MOG, inhibit multiple enzymes in glutamine metabolism and selectively kill MCT2-expressing cancer cells.
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Diversifying bases

September 17th, 2018 by Yiyun Song

Diversifying bases

Diversifying bases, Published online: 17 September 2018; doi:10.1038/s41589-018-0141-1

Diversifying bases

A new target for thalidomide

September 17th, 2018 by Peter G. Wells

A new target for thalidomide

A new target for thalidomide, Published online: 17 September 2018; doi:10.1038/s41589-018-0134-0

One mechanism of thalidomide teratogenicity involves binding to the CUL4–CRBN E3 ubiquitin ligase complex, which then mediates the degradation of transcription factors. New studies reveal that species-specific variants of the transcription factor SALL4 are differentially ubiquitinated and degraded via the thalidomide-bound complex.

Cost–benefit analysis

September 17th, 2018 by Grant Miura

Cost–benefit analysis

Cost–benefit analysis, Published online: 17 September 2018; doi:10.1038/s41589-018-0139-8

Cost–benefit analysis

T cell receptor cross-reactivity expanded by dramatic peptide–MHC adaptability

September 17th, 2018 by Timothy P. Riley

T cell receptor cross-reactivity expanded by dramatic peptide–MHC adaptability

T cell receptor cross-reactivity expanded by dramatic peptide–MHC adaptability, Published online: 17 September 2018; doi:10.1038/s41589-018-0130-4

Structural analysis shows that cross-reactivity of the T cell receptor DMF5 is governed by adaptability of the peptide antigen, which can undergo TCR-binding-induced frameshifting forcing the peptide C terminus to extend from the MHC-binding groove.
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Post-translational site-selective protein backbone α-deuteration

September 17th, 2018 by Sébastien R. G. Galan

Post-translational site-selective protein backbone α-deuteration

Post-translational site-selective protein backbone α-deuteration, Published online: 17 September 2018; doi:10.1038/s41589-018-0128-y

A chemical method for site-selective deuterium exchange at protein backbone α-carbons, involving conversion of cysteine to dehydroalanine and then to deuterated cysteine, is used to explore the mechanism of a model protein bioconjugation reaction.