Many cellular processes are regulated through the conditional association of existing proteins, motivating methods that provide precise spatial control over protein proximity. Controlling and imaging ...

Abstract. Intracellular delivery of functional proteins is emerging as a powerful strategy to interrogate and control cellular pathways with high spatial a

An alkyne-tagged ethanolamine analog (AlkEA) enables bioorthogonal, metabolic labeling of endogenous phosphatidylethanolamine (PE) and its protein modifications. AlkEA is incorporated into PE via the...

Aberrant protein-protein interactions (PPIs) drive myriad diseases. Inhibiting these PPIs often relies on discovering molecules that bind to one of the proteins and hoping that this binding inhibits t...

Developing molecules that selectively bind targets of interest remains a critical bottleneck in biological research and biotechnology. Here, we present a workflow that leverages the Phage-Assisted Non-Continuous Selection for Binders (PANCS-Binders) technology for rapid de novo binder discovery. To directly assess the speed and utility of the approach, we pursued three cancer-related targets: NSD3, NMNAT2, and CSF1R. Within 26 days, the PANCS-Binders workflow yielded sequence- and function-verified binders for all three targets with nano-to-micromolar affinities. By incorporating an NSD3 binder into an engineered E3 ligase, RNF8, we developed an NSD3 degrader that potently depleted endogenous NSD3 and inhibited colorectal cancer cell proliferation. We then applied this degrader to reveal previously unknown NSD3 dependencies in ovarian cancer cell lines, uncovering new therapeutic vulnerabilities. Together, our work establishes a robust workflow for accelerated binder discovery and demonstrates how binders can expedite chemical biology discovery and biotechnology development.

Protein binders are fundamental tools in chemical biology, key components of biotechnologies, and the foundation of biologics-based medicines. However…

RNAs preferentially localize across virtually every subcellular compartment, from membrane-bound organelles, membrane-less condensates and even the ce…

We are a dynamic, interdisciplinary, medium-size lab working at the interface of chemistry and biology. We work on the development of probes to visualize and control biological processes in living sys...

Optical manipulation of proteins is central to modulating and characterizing biomolecular functions in cell biology, but tools based on natural proteins are difficult to reconfigure for desired photoc...

A modular platform enables the generation of fluorescent metal ion indicators with tunable emission colors and precise subcellular localization. Conjugation to self-labeling proteins yields bright, c...

Nature Communications - Lin and colleagues present high-affinity split-HaloTag pairs for protein tagging and multiplexed labelling. This versatile system allows protein visualisation with diverse...

Protein binders are fundamental tools in chemical biology, key components of biotechnologies, and the foundation of biologics-based medicines. However…

Combinatorial use of an antibody–reporter enzyme conjugate and a fluorescence probe activated by the enzyme is a powerful strategy for fluorescence-guided cancer surgery. However, conventional probes ...

Targeting intracellular signaling molecules that translocate to the nucleus is a promising approach for peptide-based therapeutics. Here, we focused on Smad2/3, key mediators of TGF-β signaling that act as transcription factors upon nuclear entry. To inhibit their nuclear localization, we delivered an Smad2/3-binding SARA peptide into the cytoplasm using our previously developed cell-penetrating carrier, cpPG. A conjugate, SARA-cpPG, was synthesized by linking the SARA peptide to Mal-DKDKC12-K5, a cpPG derivative with an N-terminal maleimide. In A549 cells, SARA-cpPG showed uptake over 20-fold higher than that of the SARA peptide alone and retained cytoplasmic localization. Functionally, SARA-cpPG suppressed TGF-β1-induced actin polymerization and cell migration, comparable to the effects of receptor kinase inhibitor LY2157299. These effects were not observed with cpPG alone or a control conjugate (SARAm-cpPG) containing a nonbinding mutant peptide. Mechanistic studies revealed that SARA-cpPG did not inhibit Smad2/3 phosphorylation but reduced TGF-β target gene expression, suggesting a blockade of nuclear translocation. This suppression was absent in treatments with SARAm-cpPG, cpPG alone, or a non-cytoplasm-specific carrier conjugate (SARA-R8). These findings demonstrate that cpPG enables efficient cytosolic delivery of functional peptides and supports a strategy for intracellular peptide therapeutics targeting nuclear signaling pathways.

Phosphatidylinositol 4-phosphate (PI4P) is a fundamental phosphoinositide that controls a variety of cellular processes, including signaling, membrane…

Small-molecule fluorescent probes that selectively stain the Golgi apparatus in living cells are valuable tools for investigating Golgi-associated bio…

Combining bioorthogonal protecting groups with localized catalysts that can unmask them is a powerful approach to spatially and temporally modulate molecular activity. Enzymes are appealing catalysts ...

Tan and colleagues develop DNA nanodevices to detect the pH of the lysosomal outer surface, observing an acidic layer generated by TMEM175 that regulates lysosome positioning in response to changes in...

Coupling an optogenetic lipid-modifying enzyme with proximity labeling reveals protein networks and mechanisms regulating lipid homeostasis in the membranes of target organelles.

Rhodamine dyes conjugated to targeting ligands can yield exceptionally bright fluorescent probes for live-cell imaging. However, the limited permeability of such rhodamine derivatives restricts their ...

Compartmentalization by organelles and the dynamic control of protein localization within these compartmentalized spaces are key mechanisms for regulating biological processes in eukaryotic cells. Here, we present a bottom-up approach for constructing cell-sized liposomes (giant unilamellar vesicles, GUVs) encapsulating an artificial organelle with chemically controlled protein localization. In this system, proteins fused to Escherichia coli dihydrofolate reductase are rapidly recruited on demand from the inner solution to the interior of a DNA-droplet-based (“nucleus”-like) organelle within GUVs upon addition of a synthetic, DNA-binding trimethoprim derivative to the external solution. By coupling this system with a sequence-specific protease, we constructed a synthetic cell platform that enables chemically induced, multistep cascade reactions─including protein relocalization, organelle-specific enzymatic activity, and product release from the organelle─that culminate in the control of synthetic-cell phenotypes, such as pore formation in the GUV membrane. This work provides a versatile platform for the bottom-up creation of eukaryotic-like synthetic cells with sophisticated and programmable functions.

Creating artificial organelles that sequester and release specific proteins in response to a small molecule in mammalian cells is an attractive approach for regulating protein function. In this work, ...

Cellular phenomena such as signal integration and transmission are based on the correct spatiotemporal organization of biomolecules within the cell. Therefore, the targeted manipul...

Induced proximity modalities encompass monovalent and bifunctional agents, such as molecular glues and proteolysis-targeting chimeras, that induce an interaction between biomolecules to functionally m...

This is the open recruitment information for School of Science, the University of Tokyo.

We are a dynamic, interdisciplinary, medium-size lab working at the interface of chemistry and biology. We work on the development of probes to visualize and control biological processes in living sys...

This Special Issue in _ACS Chemical Biology_ will highlight the latest advancements and perspectives in the chemical biology of lipids and lipidation. Submit your manuscript by May 31, 2026.

Proceedings of the National Academy of Sciences (PNAS), a peer reviewed journal of the National Academy of Sciences (NAS) - an authoritative source of high-impact, original research that broadly spans...

Phosphoinositide signaling is a major cellular mechanism controlling cancer cell viability, proliferation, and survival. Yet, inhibition of lipid kinases that produce oncogenic phosphoinositides has afforded only a limited number of efficacious drugs attributed in large part to on-target toxicity resulting from the pleiotropic effects of these signaling lipids. Targeting the specific phosphoinositide effector pathways via competitive inhibitors of phosphoinositide-recognizing pleckstrin homology (PH) domains represents a relatively unexplored means to achieve greater specificity. Herein, we present the discovery from in silico screening, structure–activity relationship (SAR) optimization, and cellular characterization of novel phosphoinositide-competitive inhibitors of the pleckstrin homology domain-containing A (PLEKHA) family. These compounds induce cytotoxic effects in BRAF and NRAS mutant melanoma cells, consistent with on-target inhibition, and the most potent compound is activated by endogenous esterase activity, suggesting that prodrug esters represent a viable strategy for targeting the phosphoinositide-binding pockets of the PLEKHA family of PH domains.

An approach combining bioorthogonal chemistry with genetically encoded fluorogen-activating proteins enables subcellular imaging of phospholipids and glycans, as well as the visualization of lipid tra...