Nature Chemistry presents a Focus which explores the origins of RNA and its role in contemporary biological systems. The collection of articles reveal new insights into what early Earth might have looked like and how life first emerged.
Targeted protein degradation: You can glue it too! pp452 - 453 Michal J Walczak, Georg Petzold and Nicolas H Thoma doi:10.1038/nchembio.2355 Proteolysis-targeting chimera (PROTACs) are synthetic molecules that recruit neo-substrate proteins to a ubiquitin ligase for ubiquitination and subsequent degradation. Structural insight into the VHL-MZ1-BRD4 complex reveals how the rationally designed MZ1-PROTAC molecule mediates degradation of an unnatural protein substrate.
Microbiology: A new language for small talk pp453 - 454 Yi-Ming Shi and Helge B Bode doi:10.1038/nchembio.2362 A new signal-receptor pair involved in regulating biofilm formation and virulence was detected in Vibrio cholerae. Both the signal and the transcription factor belong to common classes of natural products and receptor proteins, suggesting widespread importance of related systems in nature.
A highlight of the knowledge derived in large part from structural work on physical motions and chemical interactions involved in voltage sensing, pore opening, ion conductance and selectivity, and voltage-dependent inactivation mechanisms of the voltage-gated channels NaV and CaV.
An automated method for solid-phase polypeptide synthesis capitalizes on rapid amide bond formation to enable the production of multiple traditionally difficult-to-synthesize sequences with both high yield and high purity.
Characterization of a family of Stigonematales (Stig) cyclases that catalyze stereoselective intramolecular C-C bond formation reveals the enzymatic origins of the complex stereochemical patterns in hapalindole and fischerindole alkaloids. Chemical compounds
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RODEO, an algorithm developed for RiPP natural product discovery, was applied to map out the gene clusters that encode and tailor lasso peptides and led to the identification and characterization of several new lasso peptide topologies. Chemical compounds
Mass spectrometry analysis combined with in vitro assays reveals that SPINDLY is an O-fucosyltransferase that modifies the growth repressor DELLA and consequently enhances its activity to regulate transcription of target genes.
Two screening approaches converge on capzimin, a first-in-class inhibitor of the Rpn11 protease component of the 19S proteasome. Capzimin stabilizes polyubiquitinated substrates, induces the unfolded protein response, and blocks proliferation of cancer cells. Chemical compounds
The application of strand-specific total RNA sequencing combined with metagene analysis enables detection of small-molecule-mediated effects on transcription initiation, elongation or RNA processing, and reveals that isoginkgetin blocks transcriptional elongation.
The structure of the TS (formerly twister sister) ribozyme reveals details about its catalytic mechanism of nucleolytic self-cleavage using a hydrated magnesium ion, and illustrates key differences between it and the related twister ribozyme.
The description of the crystal structure of the Brd4 PROTAC compound MZ1 in complex with the human E3 ubiquitin ligase VHL and the Brd4 bromodomain shines new light onto how PROTACs work and enables design of degraders with increased selectivity for Brd4. Chemical compounds See also:News and Views by Walczak et al.
High-throughput screening identifies opioid compounds and prodynorphin-derived peptide agonists of the G-protein-coupled receptor MRGPRX2 and informs a homology model that is used for in silico screening to find a small-molecule probe that provokes degranulation in mast cells, which express this receptor. Chemical compounds
Metagenomic analysis and functional characterization of biosynthetic genes uncovers the basis for widespread polybrominated diphenyl ether biosynthesis in cyanobacterial endosymbionts of marine Dysideidae sponges. Chemical compounds
Structural and functional characterization of a [NiFeSe] hydrogenase and its conversion to the [NiFe] type by mutagenesis indicate roles for the selenocysteine residue in metal incorporation, catalysis, and protection against oxidative deactivation.
A new autoinducer-receptor pair, 3,5-dimethylpyrazin-2-ol (DPO)-VqmA, acts in parallel to canonical Vibrio cholerae quorum-sensing pathways. Downstream of VqmA is the small RNA target VqmR, which, like DPO, represses genes required for biofilm formation and toxin production. Chemical compounds See also:News and Views by Shi & Bode
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