Reviews & Analysis

Development of highly specific kinase inhibitors has been a long-standing challenge in chemical biology. The structural and mechanistic characterization of an Erk1/2 kinase inhibitor provides new strategies to develop specific kinase inhibitors by targeting a binding pocket adjacent to the ATP binding site.

Ionotropic glutamate receptors are ligand-gated ion channels that mediate excitatory neurotransmission, which is crucial for memory and learning. New cryo-electron microscopy structures of these receptors trapped in distinct functional states provide remarkable insight into conformational changes triggered by agonist binding.

Besides signaling from the plasma membrane, evidence for noncanonical signaling by GPCRs from internal compartments has recently emerged and is highlighted in this Perspective. For the well-studied PTHR, agonists stabilize a distinct receptor conformation within endosomes, leading to sustained signaling.

The application of macrocycles to previously undruggable targets has aroused a great deal of interest in this structural class. Recent studies advance our understanding of the way macrocycles bind protein targets and provide new strategies and tools to generate peptide-based macrocycles.

Conventional allosteric modulators of G protein–coupled receptors (GPCRs) bind their target from the extracellular site. A new study shows that a GPCR's intracellular face can likewise be exploited. In particular, they sensitize a class B GPCR for activation by a hardly active peptide-hormone metabolite.

The gene cluster that produces the sponge-derived cytotoxin calyculin A has been located in an uncultivated bacterial symbiont. Biochemical analyses reveal a pyrophosphorylated protoxin as the true biosynthetic product and suggest that calyculins result from activated chemical defense.

Comprehensive selectivity profiling is key for the development of safe drugs. Few current methods are capable of profiling large compound sets against entire target classes. The new EnPlex method expands the existing toolbox, allowing for the surveying of the serine hydrolase enzyme family.

Therapeutic drug monitoring is vital for maintaining drug concentrations within the body in real time, maximizing therapeutic effects while minimizing the risk of harmful overdosing or wasteful underdosing. Semisynthetic fusion proteins now provide a straightforward strategy for drug monitoring by simply taking a picture of glowing paper.

Recent studies have identified the existence of modified cytosine bases in DNA that result from ten eleven translocation (Tet)-mediated oxidation of 5-methylcytosine. The demonstration that Tet oxidizes thymine to 5-hydroxymethyluracil has implications for our current view of DNA metabolism.

A study in this issue reports the 5-HT₆ receptor as a new cyclin-dependent kinase 5 (Cdk5) substrate and reveals its noncanonical pathway, which mediates neuronal differentiation in hippocampus and striatum by interacting with Cdk5 and Cdc42 in an agonist-independent manner.

There has been a strong effort to devise strategies to interfere with oncogenic Ras for cancer treatment. A review of recent advances in the development of small-molecule inhibitors that impair either Ras localization or protein interactions provides new optimism in this field.

Carbonates are known to exist in natural products, but their biosynthesis has not been linked to any enzymes. An unusual fungal Baeyer-Villiger monooxygenase CcsB is now revealed to catalyze an in-line carbonate formation via a two-step mechanism of oxygen atom insertions.

Deciphering the molecular basis of HCN channel regulation by cGMP leads to the serendipitous discovery of cyclic dinucleotides as potent inhibitors of I_f current in the heart.

The phytohormone abscisic acid (ABA) has a central role in adaptive responses of plants to abiotic stress. A new ABA antagonist offers a promising tool to study ABA signaling and adaptation to abiotic stress in diverse plants, including crops.