Cell Chemical Biology

Cellular metabolism encompasses a complex array of interconnected biochemical pathways that are required for cellular homeostasis. When dysregulated, metabolism underlies multiple human pathologies. At the heart of metabolic networks are enzymes that have been historically studied through a reductionist lens, and more recently, using high throughput approaches including genomics and proteomics. Merging these two divergent viewpoints are chemical proteomic technologies, including activity-based protein profiling, which combines chemical probes specific to distinct enzyme families or amino acid residues with proteomic analysis...

In this issue of Cell Chemical Biology, Peng and Weerapana1 report the combination of chemoproteomic and proximity-based labeling approaches to identify cysteines in nuclear proteins that are reactive toward electrophilic probe compounds. They apply this novel technology to identify proteins that are localized to the nucleus and chromatin upon probe labeling.

Bioorthogonal chemistry was deservedly recognized with the 2022 Nobel Prize in Chemistry, having transformed the way chemists and biologists interrogate biological systems in the past twenty years. This Voices piece asks researchers from a range of backgrounds: what are some major challenges and opportunities facing the field in coming years?

In this Stories piece, Sigrid Nachtergaele-an assistant professor at the Yale University Department of Molecular, Cellular, and Developmental Biology-shares her experience and efforts to cut barriers for the next generation of aspiring scientists.

Continuing the celebration of Cell Chemical Biology's 30th anniversary, this focus issue presents the spectrum of ways that bioorthogonal chemistry empowers biological and biomedical studies. The following opinion pieces, reviews, and research articles highlight specific approaches and insights that are key to addressing biological questions.

In this issue of Cell Chemical Biology, Chakraborty et al.1 employ a deep mutational screening analysis of 3,500 single point mutations in every residue in Src kinase's catalytic domain to determine which residues are critical for conferring ATP-competitive inhibitor resistance. They identify a dynamically controlled resistance site.

In this issue of Cell Chemical Biology, Lane et al.1 introduce a transgene-based system to express fusion proteins that recruit transcription factors to E3 ligases. This approach expands the target repertoire for engineered cell therapies as exemplified by the targeting of SMAD proteins to overcome a TGFβ-mediated suppressive mechanism that weakens anti-tumor responses.

In this issue of Cell Chemical Biology, Rodencal et al.1 report that cell-cycle arrest by p53 stabilizers or CDK4/6 inhibitors (CDK4/6i) can lead to phospholipid remodeling and hence sensitize cancer cells to GPX4 inhibitor (GPX4i)-triggered ferroptosis. This study suggests a novel cancer therapeutic strategy combining CDK4/6i with GPX4i.

In an interview with Samantha Nelson, a scientific editor for Cell Chemical Biology, the authors of the review entitled "Convergent impact of vaccination and antibiotic pressures on pneumococcal populations" share their perspectives on life as scientists.

Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) are a class of cancer drugs that enzymatically inhibit PARP activity at sites of DNA damage. Yet, PARPi function mainly by trapping PARP1 onto DNA with a wide range of potency among the clinically relevant inhibitors. How PARPi trap and why some are better trappers remain unknown. Here, we show trapping occurs primarily through a kinetic phenomenon at sites of DNA damage that correlates with PARPi koff . Our results suggest PARP trapping is not the physical stalling of PARP1 on DNA, rather the high probability of PARP re-binding damaged DNA in the absence of other DNA-binding protein recruitment...

In this Stories piece, Megan Ken, a Fellow at The Scripps Research Institute, discusses the importance of inclusion, mentoring, and creativity to discovery and growth in science.

No abstract text is available yet for this article.

CAG-repeat expansions underlie fatal neurodegenerative disorders. In a lodestar study published in a recent issue of Nature, Sun et al.1 identify a writer and eraser of N1 -methyladenosine (m1 A) modifications of CAG-repeat RNA. They establish that m1 A modifications in CAG-repeat expanded RNA promote neurodegeneration and aberrant phase transitions of TDP-43. These findings suggest therapeutic strategies for CAG-repeat expansion disorders.

In the first of many thematic issues marking the 30th anniversary of Cell Chemical Biology, we highlight the contribution of chemical biology to RNA biology in a special issue on RNA modulation. We asked several leaders in the field to share their opinions on the current challenges and opportunities in RNA biology.

In this editorial, the Cell Chemical Biology editors reflect on the 30th anniversary of the journal and introduce the special issue on RNA modulation.

Pathogenic mycobacteria are a significant cause of morbidity and mortality worldwide. The conserved whiB7 stress response reduces the effectiveness of antibiotic therapy by activating several intrinsic antibiotic resistance mechanisms. Despite our comprehensive biochemical understanding of WhiB7, the complex set of signals that induce whiB7 expression remain less clear. We employed a reporter-based, genome-wide CRISPRi epistasis screen to identify a diverse set of 150 mycobacterial genes whose inhibition results in constitutive whiB7 expression...

Structural dynamics of human immunodeficiency virus 1 (HIV-1) envelope (Env) glycoprotein mediate cell entry and facilitate immune evasion. Single-molecule FRET using peptides for Env labeling revealed structural dynamics of Env, but peptide use risks potential effects on structural integrity/dynamics. While incorporating noncanonical amino acids (ncAAs) into Env by amber stop-codon suppression, followed by click chemistry, offers a minimally invasive approach, this has proved to be technically challenging for HIV-1...

Methyl ketone (MK)-ascarosides represent essential components of several pheromones in Caenorhabditis elegans, including the dauer pheromone, which triggers the stress-resistant dauer larval stage, and the male-attracting sex pheromone. Here, we identify an acyl-CoA thioesterase, ACOT-15, that is required for the biosynthesis of MK-ascarosides. We propose a model in which ACOT-15 hydrolyzes the β-keto acyl-CoA side chain of an ascaroside intermediate during β-oxidation, leading to decarboxylation and formation of the MK...

RNA secondary structure plays essential roles in encoding RNA regulatory fate and function. Most RNAs populate ensembles of alternatively paired states and are continually unfolded and refolded by cellular processes. Measuring these structural ensembles and their contributions to cellular function has traditionally posed major challenges, but new methods and conceptual frameworks are beginning to fill this void. In this review, we provide a mechanism- and function-centric compendium of the roles of RNA secondary structural ensembles and minority states in regulating the RNA life cycle, from transcription to degradation...

NLRP1 is an innate immune receptor that detects pathogen-associated signals, assembles into a multiprotein structure called an inflammasome, and triggers a proinflammatory form of cell death called pyroptosis. We previously discovered that the oxidized, but not the reduced, form of thioredoxin-1 directly binds to NLRP1 and represses inflammasome formation. However, the molecular basis for NLRP1's selective association with only the oxidized form of TRX1 has not yet been established. Here, we leveraged AlphaFold-Multimer, site-directed mutagenesis, thiol-trapping experiments, and mass spectrometry to reveal that a specific cysteine residue (C427 in humans) on NLRP1 forms a transient disulfide bond with oxidized TRX1...