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Structure and mutagenesis of the colibactin-activating peptidase ClbP reveals a dimer with a substrate-binding transmembrane domain and a conserved polar network in its periplasmic domain that enforces selectivity for d-asparagine prodrug motifs.
A substrate-guided design strategy generated highly potent inhibitors of the biosynthesis of the genotoxin colibactin by human gut bacteria. These inhibitors also enable a generalizable approach for chemically guided natural product discovery.
Prostate tumors, resistant to current antiandrogen therapies, represent a serious clinical challenge. A new report identifies androgen-receptor-dependent liquid condensates as being responsible in part for therapeutic resistance, but, encouragingly, also reveals a novel vulnerability amenable to drug targeting.
The fungal sterol receptor and transcription factor Upc2 activates the transcription of ergosterol biosynthesis genes in response to ergosterol depletion in yeast. A structural and biochemical study reveals an Hsp90-dependent translocation activation mechanism of Upc2, with implications for triazole antifungal resistance.
The structure of fungal sterol receptor Upc2 reveals ligand specificity and mechanism of transcriptional activation contributing to azole resistance. A regulatory role of Hsp90 chaperone in ergosterol-dependent translocation of Upc2 was discovered.
A small molecule was developed that disrupted the lipid–SH2 domain interaction of the spleen tyrosine kinase (Syk), suppressed oncogenic activities in acute myeloid leukemia cell lines and was refractory to drug resistance.
Phase separation of androgen receptor underlies mutation-mediated antiandrogen resistance. A phenotypic screen enabled the discovery of ET516, which disrupts androgen receptor phase separation and effectively suppresses the growth of prostate cancer.
A precise adenine base editor variant, ABE9, was developed to generate single adenine transition at pathogenic homopolymeric adenine sites with minimal DNA/RNA off-target effects, suggesting promising potential for gene therapeutics.
Unbiased metabolomics revealed the conversion of serotonin into N-acetylserotonin-derived glucosides by an intestinal carboxylesterase in Caenorhabditis elegans, which suggests an unappreciated role of the gut in modulating 5-HT signaling.
Untargeted comparative metabolomics revealed serotonin biosynthesis and metabolism pathways in nonneuronal tissues that contribute to established serotonin-dependent phenotypes in C. elegans.
The gut microbiota has a key role in protecting hosts from pathogens. A new study identified a gut microbiota-derived bile acid (chenodeoxycholic acid) that inhibits bacterial infection by interacting with a regulatory protein necessary for the expression of virulence factors.
Aminoadamantane compounds, delivered to cells via binding to viroporin channels, induce S-nitrosylation of the ACE2 protein, inhibiting binding to SARS-CoV-2 spike protein and viral infection.
An INSPIRE platform for therapeutic regulators and sensors, based on split human domains binding physiological or clinically approved compounds, has been developed and demonstrated on several human proteins in a relevant ligand concentration range.
Cryo-EM structures of the mouse TRPV2 channel, combined with electrophysiology and simulations, reveal that endogenous cholesterol binds to the vanilloid binding pocket to inhibit this channel, while exogenous 2-APB binds to same pocket to open TRPV2.
Mukherjee et al. report that AcrIF24 is an Acr-Aca fusion protein that inhibits the Csy complex and suppresses transcription from the acrIF23–acrIF24 promoter, and they present cryo-EM structures to reveal the mechanism for both roles of AcrIF24.
DNA-templated compound library screening and structure-guided hit optimization resulted in the identification of selective macrocyclic inhibitors of cyclophilin isoforms CypD and CypE.
Evernimicin, an antibiotic of the orthosomycin class, inhibits bacterial translation by preventing ribosomes from polymerizing specific amino acid motifs, and controls the expression of resistance genes via such context-specific action.
Chemigenetic combination of a synthetic ion-recognition motif and a protein-based fluorophore resulted in the development of calcium and sodium ion sensors.
