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The plant AUG-stop element in the 5′ UTR acts as a boron concentration sensor, regulating downstream ORF translation. Here, structural and biochemical analyses show that a high concentration of borate fixes eRF1 on 80S ribosomes, preventing sliding through downstream of AUG-stop elements.
The rules for designing cyclic peptides with drug-like properties are unclear. Two studies now show how cyclic peptide libraries can be created to optimize properties such as cell permeability before screening for binding activity. The approach has led to a macrocyclic peptide inhibitor for KRAS that has reached clinical trials.
The authors determined a set of structures of the methylase Cfr-methylated 70S ribosome with iboxamycin and tylosin, two antibiotics that evade Cfr-mediated drug resistance, and revealed two distinct mechanisms by which small molecules can maintain their ability to engage the Cfr-methylated ribosome.
Hanswillemenke, Hofacker and colleagues developed a proximity labeling-based method to identify protein interactome of small molecules and RNA drugs within living cells, facilitating the design and development of RNA drugs with enhanced pharmacological properties.
Sirtuins remove post-translationally added acyl groups from protein lysines. New work shows the surprising metabolic fate of acyl groups removed from mitochondrial proteins—they react nonenzymatically with essential polyamine spermidine, forming previously unknown monoacylated N-glutarylspermidines and diacylated N-glutaryl,N-acetylspermidines.
A new design for vaccines consisting of reorienting the viral glycoprotein in an ‘upside-down’ configuration broadens immune responses to diverse influenza subtypes and serves as a proof of concept for designing a universal flu vaccine.
Screening of a chemical library identifies a novel ferroptosis inhibitor that directly interferes with the formation of intracellular membrane contacts between the endoplasmic reticulum (ER) and mitochondria (ERMCS), commonly referred to as mitochondria-associated membranes (MAMs).
A small molecule, CGI1746, was identified to block ferroptosis acting through the sigma-1 receptor, a chaperone primarily at endoplasmic reticulum–mitochondria contacts to mediate calcium transfer.
Qin et al. find that cell detachment induces condensation of LATS2, a core kinase of the Hippo pathway. These LATS2 condensates protect LATS2 from degradation by the ubiquitin–proteasome system, thereby promoting the assembly of Hippo signalosomes for pathway activation.
Nature has evolved elegant enzymatic strategies to cyclize peptides, resulting in complex macrocyclic compounds with potent biological activities. A study illustrates the diverse chemical versatility of one such remarkable enzyme family, the cytochrome P450 macrocyclases, which form new biaryl crosslinks in ribosomal peptidic natural products.
Integrated chemoproteomic development of selective small-molecule SLC15A4 inhibitors and their functional characterization establish SLC15A4 as a druggable target for autoimmune conditions.
Hernandez-Candia et al. introduce BTBolig, a chemical-based tool to manipulate biomolecular condensates, and CoSMo, a method for control of condensate maturation. When used together, the authors observe dynamic interactions of condensates with protein chaperones.
The small molecule SRI-41315 induces the degradation of the translation termination factor eRF1 to enhance stop codon readthrough. Coelho, Yip et al. reveal that SRI-41315 is a metal-dependent molecular glue that traps eRF1 on terminating ribosomes.
Identification of a small molecule (Ebio1) reveals a unique activation mechanism for the KCNQ2 potassium channel. Ebio1 induces a twist-to-open movement in the S6 helices, creating an extended channel gate with enhanced conductance.
Weng et al. developed a photocaged lysine-based gain-of-function strategy termed DeKinomics to systematically dissect kinase activity with high specificity and temporal resolution under living conditions.
Using single-molecule and biochemical methods, Göse et al. demonstrated that the helicase-like ATPase of a Type III restriction enzyme establishes DNA sliding through a sequential series of nucleoprotein remodeling steps driven by DNA translocation.
