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Peptide macrocycles are attracting increasing attention as tools for research and as potential therapeutics. The highly efficient butelase 1—homologous to proteases but specific for ligations—offers a new method for peptide cyclization.
Finding evolutionary links between protein superfamilies has proven challenging. Advanced bioinformatics tools now identify relationships across two superfolds as well as a hybrid family whose structure displays characteristics of both.
ABPP combined with quantitative MS enabled identification of specific on- and off-targets of covalent kinase inhibitors. Modifications to inhibitors that alter specificity beyond a defined window can promote kinase-independent toxicity.
BETP, a positive allosteric modulator of GLP-1R, a class B GPCR and an important therapeutic target for type II diabetes, covalently modifies two cysteine residues at the receptor's cytoplasmic face, where one of these enhances agonist-induced signaling. [In the version of the Table of Contents initially published, the labels for the BETP conditions were swapped in graphical abstract of the Nolte et al. article. The error has been corrected in the HTML and PDF versions of the Table of Contents.]
(+)-7-iso-jasmonoyl-L-isoleucine (JA-Ile) is a plant hormone involved in plant development and stress response that signals through a COI1–JAZ co-receptor complex. Structure-guided design led to the identification of a coronatine derivative that antagonizes the COI1-JAZ interaction and blocks jasmonate signaling in plants.
C-terminal extended ubiquitin species, which have been associated with neurodegenerative disorders, were thought to inhibit proteasomes resulting in reduced protein clearance. Biochemical studies now provide evidence that these ubiquitin variants primarily block the activity of the deubiqutinating enzymes.
The development of a new screening method called EnPlex allows rapid profiling of small molecules against an extensive selection of the serine hydrolase enzyme family, resulting in the identification of both off-targets and potential lead compounds.
Inclusions containing TDP43 are linked to pathologies in several neurodegenerative diseases such as ALS and FTD. Pathogenic TDP43 mutations are now found to shorten the protein's half-life in individual neurons. Stimulating autophagy with inhibitors improves TDP43 clearance and localization.
Some toxic natural products are made in deactivated forms to avoid damage to the host. Metagenomic mining of sponge symbionts and biochemical characterization now define a new inactivating mechanism in which calyculin is made as a pyrophosphate by symbiotic bacteria and cleaved to the active monophosphate by the sponge.
Polybrominated aromatic natural products are pervasive in the marine food web. Genetic and biochemical data now establish their biosynthetic origins in marine bacteria, revealing a physiological brominase that uses an unusual decarboxylative mechanism.
The addition of a Notch signaling inhibitor to both mouse and human keratinocytes bypasses the use of oncogenes and p53 to increase transcription factor mediated–pluripotent stem cell reprogramming through blocking p21 expression.
Spinach is an RNA aptamer analog of GFP that is widely used for fluorescent labeling of cellular RNAs. Crystal structures of Spinach–fluorophore complexes uncover an unusual G-quadruplex RNA fold that is involved in ligand recognition and tuning of Spinach fluorescence properties.
Drug-resistance mutations provide a classical means to identify biological targets of small molecules. A combination of next-generation DNA sequencing with CRISPR-Cas9 genome editing confirms the targets of 6-thioguanine and triptolide and offers a general approach for target identification in cells.
Finding the biological targets of small molecules remains an important challenge in chemical biology and drug discovery. A method involving high-throughput sequencing, mutational analysis and clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 genome editing identifies the targets and potential modes of compound resistance for two anticancer agents.
The combination of synthetic ligands, luminescent proteins and binding proteins converts a well-established ligand-sensing system into a tunable and quantitative reporter for drug concentrations in blood, as demonstrated with six different drugs and using a simple digital camera.
Genetic code reprogramming has generally focused on changing the translation step of protein expression, altering what each codon specifies. Mutations in the peptidyl transferase center, along with compensatory mutations in the C-termini of tRNAs, now provide an alternate method to create fully orthogonal ribosomes.
PIP2 binds via electrostatic interactions to the N terminus of the dopamine transporter (DAT) to modulate its function in dopamine efflux. This regulation is necessary for Drosophila locomotor activity induced by the DAT substrate amphetamine.
The serotonin receptor 5-HT6 interacts with a network of proteins that includes Cdk5. Functionally, Cdk5 phosphorylates the receptor at S350 and modulates its activity in inducing neuronal differentiation in a model neuroblastoma cell line and neurite growth in primary neurons.
Structure-guided peptide phage display combined with activity-based sorting results in the identification of zymogen activator peptides (ZAPtides) that selectively bind and activate the serine protease–like pro-HGF zymogen to promote Met signaling.
The allosteric binding of MSI-1436 to the intrinsically disordered C-terminal region of PTP1B promotes a conformational change to generate a compact inactive structure, validating the use of MSI-1436 to inhibit HER2-mediated tumorigenesis.
