Volume 19 Issue 1, January 2023

Small-molecule-mediated targeted protein degradation (TPD) relies on the recruitment of a target protein of interest to an E3 ligase. A new study indicates how direct target recruitment to the 26S proteasome can bypass this requirement.

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.

YcaO enzymes are able to catalyze a diverse set of reactions and have found industrial applications. New biochemical data provide the first direct evidence for the unified reaction mechanism proposed a decade ago and will inform future enzyme engineering efforts.

Engineering of a high-affinity Delta-like variant, named Delta^MAX, potently activates Notch signaling when provided in a bead-bound or cellular format, while administration as a soluble decoy inhibits signaling.

Compound library screening combined with medicinal chemistry and structural biology approaches enables the development of potent and highly selective cell-permeable small-molecule inhibitors of phosphatidylinositol 3-kinase C2α activity and function.

Enzymatically generated sulfane sulfur species called hydropersulfides terminate free radical chain reactions to prevent oxidative membrane damage and ferroptosis induction.

Chemigenetic combination of a synthetic ion-recognition motif and a protein-based fluorophore resulted in the development of calcium and sodium ion sensors.

By inserting RNA-binding domains to an active-site-proximal loop amidst CRISPR–Cas, Yang, Song et al. generate variants with enhanced collateral activity for ultrasensitive and amplification-free RNA detection when coupled with electrochemical sensing platforms.

Discovery of macrocyclic ligands to the 19S regulatory particle protein PSMD2 enables the synthesis of heterobifunctional molecules that demonstrate proof-of-concept, targeted degradation of BRD4 through direct engagement of the 26S proteasome.

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.

Fan et al. report a potent and subtype-selective TRPV3 antagonist, Trpvicin, and reveal its binding sites and mode of action for TRPV3 inhibition via high-resolution cryogenic electron microscopy structures.

Chemoproteomic analysis reveals that anti-infective bile acids directly bind and inactivate a transcriptional regulator of Salmonella virulence.

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.

YcaO enzymes carry out diverse tailoring reactions of peptide-derived natural products, such as formation of rings and incorporation of sulfur, but YcaO enzymes also catalyze peptide proteolysis using adenosine 5′-triphosphosphate as a co-factor.