Volume 18 Issue 11, November 2022

Mutant-selective KRAS-targeting drugs hold great promise for the treatment of some of the most aggressive forms of cancer. Building on the breakthrough success of KRAS-G12C inhibitors, researchers have now found a way to target another mutant KRAS with serine-modifying covalent inhibitors.

A combined structural and biochemical analysis reveals that TRIM7 E3 ligase targets viral proteins for degradation by recognizing their C-terminal glutamine (C-Gln) via its PRY-SPRY domain, providing mechanistic insight into the C-degron pathway.

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 microtubule-associated protein tau is strongly linked to Alzheimer’s disease, but the physiological functions of tau on microtubules remain unclear. New experiments reveal that tau recognizes and alters the conformation of the underlying microtubule lattice by forming envelopes that surround its surface, suggestive of a novel role for tau in cell physiology.

Photorhabdus noenieputensis (a gut microbiota symbiont of nematodes) produces a macrocyclic antibiotic, evybactin, that selectively kills Mycobacterium tuberculosis (Mtb). The Mtb membrane transporter BacA imports evybactin into the cell, where it binds to DNA gyrase and causes cell death.

The discovery of a strained β-lactone electrophile that covalently targets a KRAS G12 somatic mutation and acylates the mutant serine to suppress oncogenic signaling.

DNA-templated compound library screening and structure-guided hit optimization resulted in the identification of selective macrocyclic inhibitors of cyclophilin isoforms CypD and CypE.

The description of the cryo-EM structure of an orphan adhesion GPCR–G_s protein complex in apo state facilitates the screening and identification of potential ligands of ADGRG2.

Metabokiller is a novel, explainable AI-backed method for carcinogenicity prediction that leverages the biological and chemical properties associated with carcinogens.

Using structural and biochemical methods, Liang et al. revealed a C-terminal glutamine-end recognition mechanism of TRIM7 E3 ligases, which enables identification of substrates for TRIM7 and provides insight into the versatile functions of TRIM7 in viral infection and the C-degron pathway.

Microtubule-associated proteins tau and MAP2 cooperatively form protein envelopes that compact the underlying tubulin lattice, revealing a novel role for these proteins in altering microtubule structure.

Evybactin is an antimicrobial natural product that targets DNA gyrase, where it binds to a site overlapping with synthetic thiophene poisons and exerts selectivity for Mycobacterium tuberculosis via its transport mechanism into the cell.

Dynamic redundancy by horizontal gene transfer stabilizes gene abundances amidst compositional fluctuations in microbial communities, which suggests a means to program gene stability of complex microbiota.

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.

An RNA aptamer that selectively binds FAD over FADH₂ shifted the reduction potential of the bound cofactor, similar to flavoproteins, and was shown through structural characterization to use π–π and donor–π interactions to drive the shift.

SARS-CoV-2 spike-directed, non-neutralizing antibodies were converted into broad-spectrum inhibitors by conjugation to the SARS-CoV-2 receptor, ACE2, resulting in fusion proteins that target all SARS-CoV-2 variants of concern tested.

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.