Biology subjects

Eyal, S.

Publications and source records attributed to Eyal, S..

5 recordsLinked to original sources

bioRxiv2026

Pharmaceutical TAS2R14 Agonists Display Diverse Potency, Efficacy, and Binding-Site Sensitivity

Bitter taste receptors (TAS2Rs) are G-protein coupled receptors that detect chemically diverse compounds, including many clinically used drugs. TAS2R14 is expressed in many extraoral tissues and is activated by hundreds of ligands, including pharmaceutical drugs. Recent cryo-EM structures revealed a previously unrecognized intracellular binding pocket in TAS2R14, raising new questions regarding ligand binding modes. Here, we investigated the activation of TAS2R14 by Tamoxifen, Carbimazole, and Lidocaine using cell-based assays measuring proximal G-protein recruitment (BRET2) and downstream signaling (IP-One). Tamoxifen and Carbimazole activated TAS2R14 with EC50 values in the low micromolar range, whereas Lidocaine required substantially higher concentrations. Targeted receptor mutations were used to evaluate the contribution of extracellular and intracellular binding regions to agonist activity. Carbimazole and Lidocaine showed greater dependence on the intracellular and extracellular positions, respectively, while Tamoxifen displayed assay-dependent, but overall modest sensitivity to the tested mutations. Thus, although existing drugs can activate TAS2R14 through distinct binding modes, TAS2R14-directed repurposing will depend on whether effective local receptor concentrations can be achieved through appropriate delivery strategies.

pharmacology and toxicology↗

bioRxiv2025

Intracellular and Dual-Site Inhibition of a bitter taste GPCR

Bitter taste receptors (TAS2Rs) are G protein-coupled receptors expressed in both gustatory and extraoral tissues and activated by a broad range of compounds. TAS2R14 is among the most promiscuous members of this family, responding to many structurally diverse ligands. Cryo-electron microscopy structures of TAS2R14 have revealed agonists binding in an intracellular pocket, raising the question of the main sites of interaction for known TAS2R14 antagonists. To address this, we examined the effects of mutations at residues located in the extracellular and intracellular regions on receptor inhibition by three antagonist compounds. Mutations in the extracellular region reduced the inhibitory effect of LF22, whereas all three compounds showed reduced inhibition in the intracellular mutants. Computational co-folding of these ligands with TAS2R14 supported these observations, indicating that LF22 interacts with both top and bottom binding sites, whereas LF1 and probenecid engage predominantly the intracellular site adjacent to the G protein interface. Interestingly, LF1 is much more potent for TAS2R16 than its known inhibitor probenecid. These findings reveal distinct inhibitory mechanisms among TAS2R antagonists and provide new insights towards designing inhibitors of bitter taste.

biochemistry↗

bioRxiv2020

Algorithmic Learning for Auto-deconvolution of GC-MS Data to Enable Molecular Networking within GNPS.

Gas chromatography-mass spectrometry (GC-MS) represents an analytical technique with significant practical societal impact. Spectral deconvolution is an essential step for interpreting GC-MS data. No public GC-MS repositories that also enable repository-scale analysis exist, in part because deconvolution requires significant user input. We therefore engineered a scalable machine learning workflow for the Global Natural Product Social Molecular Networking (GNPS) analysis platform to enable the mass spectrometry community to store, process, share, annotate, compare, and perform molecular networking of GC-MS data. The workflow performs auto-deconvolution of compound fragmentation patterns via unsupervised non-negative matrix factorization, using a Fast Fourier Transform-based strategy to overcome scalability limitations. We introduce a "balance score" that quantifies the reproducibility of fragmentation patterns across all samples. We demonstrate the utility of the platform with breathomics analysis applied to the early detection of oesophago-gastric cancer, and by creating the first molecular spatial map of the human volatilome.

bioinformatics↗

bioRxiv2018

Bone Morphology is Regulated Modularly by Global and Regional Genetic Programs

During skeletogenesis, a variety of protrusions of different shapes and sizes develop on the surfaces of long bones. These superstructures provide stable anchoring sites for ligaments and tendons during the assembly of the musculoskeletal system. Despite their importance, the mechanism by which superstructures are patterned and ultimately give rise to the unique morphology of each long bone is far from understood. In this work, we provide further evidence that long bones form modularly from Sox9+ cells, which contribute to their substructure, and from Sox9+/Scx+ progenitors that give rise to superstructures. Moreover, we identify components of the genetic program that controls the patterning of Sox9+/Scx+ progenitors and show that this program includes both global and regional regulatory modules.\n\nUsing light sheet fluorescence microscopy combined with genetic lineage labeling, we mapped the broad contribution of the Sox9+/Scx+ progenitors to the formation of bone superstructures. Additionally, by combining literature-based evidence and comparative transcriptomic analysis of different Sox9+/Scx+ progenitor populations, we identified genes potentially involved in patterning of bone superstructures. We present evidence indicating that Gli3 is a global regulator of superstructure patterning, whereas Pbx1, Pbx2, Hoxa11 and Hoxd11 act as proximal and distal regulators, respectively. Moreover, by demonstrating a dose-dependent pattern regulation in Gli3 and Pbx1 compound mutations, we show that the global and regional regulatory modules work coordinately. Collectively, our results provide strong evidence for genetic regulation of superstructure patterning that further supports the notion that long bone development is a modular process.

developmental biology↗

bioRxiv2018

On the Development of Sesamoid Bones

Sesamoid bones are a special group of small auxiliary bones that form in proximity to joints and contribute to their stability and function. Sesamoid bones display high degree of variability in size, location, penetrance and anatomical connection to the main skeleton across vertebrate species. Therefore, providing a comprehensive developmental model or classification system for sesamoid bones is challenging. Here, we examine the developmental mechanisms of three anatomically different sesamoid bones, namely patella, lateral fabella and digit sesamoids. Through a comprehensive comparative analysis at the cellular, molecular and mechanical levels, we demonstrate that all three types of sesamoid bones originated from Sox9+/Scx+ progenitors under the regulation of TGF{beta} and independent of mechanical stimuli from muscles. We show that BMP4 was necessary specifically for differentiation of patella but not of lateral fabella or digit sesamoids, whereas BMP2 regulated the growth of all examined sesamoids. Next, we show that whereas patella and digit sesamoids initially formed in juxtaposition to long bones, the lateral fabella formed independently at a distance. Finally, we provide evidence suggesting that while patella detached from the femur by formation of a synovial joint, digit sesamoids detached from the phalanx by a fibrocartilage joint. Collectively, these findings highlight both common and divergent molecular and mechanical features of sesamoid bone development, thereby advancing our understanding of their evolutionary plasticity.

developmental biology↗