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Natural products and synthetic bifunctional molecules enable the development of new chemical probes that target oxysterol-binding protein (OSBP), a key player in intracellular cholesterol homeostasis and Golgi complex integrity and a potential target for metabolic disease and cancer.
Identifying the protein component of calcium signaling in specific subcellular regions presents considerable challenges. Researchers have now successfully integrated calcium indicators with proximity labeling, enabling the targeting of microdomain-specific calcium signaling.
Chemical, genetic and proteomic approaches were used to elucidate the mode of action of orpinolide, a withanolide-inspired OSBP inhibitor, revealing sterol transport as a druggable metabolic dependency in leukemia.
This Perspective proposes practical guidance to the application of AlphaFold2 for structure prediction of different classes of proteins including rigid globular proteins, intrinsically disordered proteins and alternative conformational states. The use of evaluation metrics to predict reliability of the resulting models and their integration with experimental data are also discussed.
An efficient computational pipeline starting from validated peptide assemblies has been used to design two families of α-helical barrel proteins with functionalizable channels. This rationally seeded computational protein design approach delivers soluble, monomeric proteins that match the design targets accurately and with high success rates.
An in vivo chemical screen has uncovered a potential role for a tryptophan metabolite in promoting host survival during bacterial infections through modulation of ionotropic glutamate receptors. Host-directed therapies for bacterial infections offer a largely untapped approach to treatment.
A tryptophan metabolite was identified that acts systemically to promote defense against bacterial infection by targeting kainate receptors (KARs), revealing a novel intersection between tryptophan metabolism and KARs in immune defense.
Biological nitrogen fixation requires low-potential electrons from ferredoxin or flavodoxin. Here the authors show how the soil diazotroph Azotobacter vinelandii employs the NADH:ferredoxin oxidoreductase RNF1 complex to lower the midpoint potential of the electron from NADH to reduce ferredoxin.
A photochromic dimerizer was developed for light-controlled reversible and quantitative regulation of intracellular protein localization, enabling optical control of PTEN-induced kinase 1 (PINK1)–Parkin-mediated mitophage induction.
The inaugural CRISPR-based drug Casgevy has been approved by several medical agencies, with other CRISPR-based therapies currently in clinical trials. Although there are technological hurdles to overcome, chemical biology has a vital role in developing recent breakthroughs in base editing, prime editing and epigenetic editing into future treatments.
An end-to-end pipeline generates the optimal copy number combination of genes in a biosynthetic pathway for chromosomal integration to engineer high-performing strains with genetic stability.
The kinesin-1 motor protein accesses open active and closed autoinhibited states. These states are regulated by a flexible elbow within a complex coiled-coil architecture. Now, a conformational switch has been developed by engineering the elbow to create a closed state that can be controllably opened with a de novo designed peptide to increase kinesin transport inside cells.
Fluorogenic RNA aptamers have previously been developed to enhance RNA imaging. We determined the tertiary complex structures of a newly discovered Clivia aptamer, which exhibits a small size and a large Stokes shift. Structural insights into the fluorescence activation mechanism of Clivia build a strong foundation for its efficient use in RNA imaging.
Toxic small alarmone synthetase (toxSAS) enzymes are toxic effectors of certain toxin–antitoxin modules, involved in phage defense and secretion systems. Here the authors establish the mechanism underlying toxSAS inhibition by structured antitoxins and reveal the connection between neutralization strategy and substrate specificity.
To understand the complex dynamics and diverse functions of RNA, robust technologies for labeling and imaging RNA are highly desirable. A newly developed green fluorescent aptamer named Okra enables the imaging of mRNA dynamics in living cells.
Enediyne natural products are potent antitumor antibiotics but the biosynthesis of their 1,5-diyne-3-ene core has remained enigmatic for decades. Here a diiodotetrayne is reported as a universal enediyne biosynthetic intermediate of this core, obtained upon cryptic iodination.
