Reviews & Analysis

A combination of chemical and genetic approaches has established a proof of concept in mouse models—with strong mechanistic underpinning—indicating that targeting the aberrantly recruited histone methyltransferase activity of DOT1L has therapeutic potential in aggressive leukemias driven by MLL fusion genes.

Man-made adhesives cannot match the ability of a marine mussel to affix itself to a wet rock. New insights help to describe the protein-surface bonding central to this feat of biological materials engineering.

Protein misfolding, oligomerization and aggregation are implicated in a variety of neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. New research sheds light on the process of amyloid-β aggregation in vitro, identifying nucleated conformational conversion of oligomers as the mechanism for generating amyloid fibrils.

Nature's approach to biosynthesis often involves the rapid generation of advanced, enantiopure intermediates from simple starting materials. A new, highly efficient strategy adapts this approach, using organocascade catalysis to quickly construct a key intermediate that can be converted into several complex natural products.

Homo- and heterodimerization of G protein–coupled receptors (GPCRs) have been described for numerous receptors, but their functional role has remained elusive. With a new spectroscopic assay based on protein fragment complementation, GPCR heterodimerization was demonstrated to contribute to a phenomenon called 'functional selectivity'.

Concern over exposure to the radioactive fallout from nuclear power generation is episodic; not surprisingly, it is heightened at present, following the tragedy in Japan. A primary cytotoxin cohort released in such reactor meltdowns consists of isotopes of plutonium (Pu), all radioactive. The most common valence form, Pu(IV), mimics Fe(III) in the transferrin–transferrin receptor pathway; this pathway serves as Pu's 'Trojan horse' through which to enter the body.

Bacteria communicate by sending and receiving chemical cues in a process termed 'quorum sensing'. New research shows how five feedback loops of the Vibrio harveyi quorum sensing cascade ensure signal integration and transmission fidelity, with one loop controlling signal sensitivity by regulating receptor ratios.

A potent and selective inhibitor for the protein lysine methyltransferases G9a and GLP has been discovered. This small molecule serves as a useful probe to decipher the specific role of these enzymes in the development of various diseases.

Peptide agonists of class B G protein–coupled receptors have separate segments for binding and activation. Synthesizing peptidic analogs that can be 'clicked' together allows for rapid optimization of agonist activity—as well as providing some surprises about receptor pharmacology.

Phosphomimetic mutations at huntingtin (Htt) Ser13 and Ser16 within the conserved N-terminal 17-amino-acid domain profoundly suppresses its toxicity in cell and mouse models of Huntington's disease. New research reveals that cell stress acts as a stimulus for double phosphorylation of endogenous Htt, causing its nuclear translocation, and shows that certain chemicals can target such molecular processes in Huntington's disease cell models.

Metabolic engineers have long sought a rational approach to designing hybrid organisms with unique biosynthetic capabilities. Combining in silico pathway discovery with genome-scale modeling has now provided an engineered Escherichia coli capable of producing the unnatural fermentation product 1,4-butanediol at near-commercial levels.

The combination of NMR spectroscopy and statistical mechanics represents a powerful approach to characterize the behavior of macromolecules. Two recent studies demonstrate that the application of this strategy to analyze chemical shift measurements can reveal complex mechanisms of protein regulation.

Spiroacetal substructures introduce important conformational constraints into bioactive polyketide natural products. New research reveals a two-enzyme team responsible for this molecular origami in reveromycin A biosynthesis.

Antibiotics are critical defenses in the fight against bacterial infections, but they can also be used as probes to explore basic microbiology, including cell division, stress responses and cell wall biosynthesis, and will be valuable tools in deciphering bacterial networks and complexity.

Bacteria oscillate between the planktonic and biofilm states through many hierarchically organized networks that respond to environmental cues. Recent research describes how a bacterial toxin-antitoxin system mediates this transition by controlling bacterial motility in response to extracellular stress.

Riboswitches are so named because they switch gene expression on or off in response to binding of specific metabolites. Two evolutionarily and mechanistically divergent riboswitches that recognize the universal methyl donor S-adenosylmethionine are shown to undergo dynamic conformational sampling before ligand binding.

STIM proteins are ubiquitous endoplasmic reticulum Ca²⁺ sensors that rapidly translocate to couple with 'store-operated' Orai Ca²⁺ channels when luminal Ca²⁺ levels are low. STIM1 also senses heat changes, which trigger a similar translocation and prime STIM1 to activate Orai, suggesting that STIM1 functions as a sensor of multiple stress signals.