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An in silico directed evolution approach using first principles of allostery predicts the effects of protein sequence and structure variation on constitutive activity and ligand response in GPCRs.
The ability to engineer synthetic signaling networks has proven challenging for synthetic biology. A breakthrough design strategy shows that bacterial two-component-system-derived parts can be grafted into mammalian cells to create programmable phosphorylation circuitry.
Phenotypic screening is an engine of discovery for bioactive small molecules and can unravel novel mechanisms and pathways controlling cellular physiology. A recent study reveals the CPSF complex as a pharmacologically tractable target of JTE-607 and context-specific cancer dependency.
Molecular-glue-mediated proximity-induced degradation now allows unprecedented therapeutic targeting of previously undruggable proteins. Structures showing how aryl-sulfonamides mediate recruitment of the splicing factor RBM39 to the E3 CRL4DCAF15 broaden the mechanistic principles by which molecular glues target ubiquitylation.
Actin cytoskeletal structures are essential for many cellular processes, and cofilin is a key protein for the assembly of these highly dynamic structures. A new cofilin construct enables precise optogenetic control of actin assembly in live cells.
The last step of archaeosine biosynthesis was found to involve two enzymes, the previously known ArcS with lysine transfer activity and a novel identified radical SAM enzyme named RaSEA.
The regulation of brain iron homeostasis, previously thought to be cell autonomous and modulated by local factors in the interstitial fluid, is reported by Wang et al. to be strongly influenced by axonal transport of iron in an activity-dependent and unidirectional manner between functionally associated regions. The supply of iron from the ventral hippocampus to the middle prefrontal cortex subserved an anxiolytic phenotype and mediated the neuropharmacological actions of diazepam and lithium chloride in rodent models.
This Perspective focuses on the chemical basis of ferroptotic cell death, discussing the prominent role of spontaneous chemical reactions, how they depend on enzyme-catalyzed processes and how to exploit this interplay for therapeutic benefit.
Riboswitches enable microbes to rapidly respond to changing levels of metabolites. A high-throughput platform reveals how RNA structural transitions kinetically compete during transcription in a new mechanism for riboswitch function.
The growth and guidance of axons dictate their trajectories and are critical for neural-circuit formation. Research in this issue uncovers a new mechanism for regulation of axon growth and guidance that acts via extracellular phosphorylation of a receptor.
This Perspective summarizes recent discoveries that have laid the foundation for targeted degradation therapeutics and discusses the current state of understanding and consideration involved in developing these protein degraders.
Cytoplasmic dynein is a complex molecular motor that steps along microtubules. Advanced biophysical measurements reveal a surprising role for the dynein tail domain in the allosteric control of dynein’s mechanochemistry within assemblies composed of multiple dynein motors.
A comprehensive genetic screen reveals new cellular trafficking factors and linker-dependent requirements for antibody–drug conjugate (ADC) cytotoxicity. These new insights may guide the design of optimized ADCs.
An unusual terpene nucleoside, 1-TbAd, made by pathogenic mycobacteria acts as an antacid to block mycobacterial degradation in host cell vacuoles. The antacid activity acts to reduce acidity by neutralizing the pH of these degradative cell organelles.
Analysis of recent X-ray crystallography data on eukaryotic glycosyltransferases in complex with acceptor and donor substrates reveals structural features that govern substrate specificity and glycosylation site selection.
Asymmetric cell division, which generates daughter cells with distinct characteristics, is a mechanism for creating complex systems through cellular differentiation. Two studies in this issue develop synthetic platforms that program spatial localization of genetic material or signaling molecules to enable asymmetric cell division in Escherichia coli.
A new sugar-based cysteine-reactive probe, combined with competitive activity-based protein profiling (ABPP), enables site-centric target deconvolution of itaconate in native proteomes, shedding light on a novel mechanism of action for this important immunoregulatory metabolite in inflammatory macrophages.
The N6-methyladenosine modification on RNA affects almost all steps of RNA metabolism. A new approach, using the CRISPR-based technology to modulate m6A level in mRNA, enables direct functional interrogation of site-specific m6A.
Hetz et al. discuss recent advances in the identification and optimization of small molecules targeting the unfolded protein response and the application of these small molecules in cancers, neurodegeneration and metabolic diseases.
Using knowledge of their evolutionary origin, an automated platform has been developed to provide accurate de novo structural predictions of products from trans-acyltransferase polyketide synthases.
