ArticleNeuron2021
A Non-covalent Ligand Reveals Biased Agonism of the TRPA1 Ion Channel.
Article in Neuron, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.
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Who cites it
52 citing papers in PubMed, 91 citations in OpenAlex.
- Drafting the calmodulation playbook: Emerging structural insights into transient receptor potential channel regulation by calmodulin.The Journal of physiology · 2026Review
- Europium Metal Complex [Eu(dbm)Chemistry & biodiversity · 2026Article
- Targeting TRPA1 with Novel Synthetic Compounds Based on Different Scaffolds to Reduce Acute and Chronic Pain.International journal of molecular sciences · 2026Article
- Physiological functions and pharmacological targeting of transient receptor potential channels.Pharmacological reviews · 2025Review
- Antinociceptive and Anti-inflammatory Effect of Nicandrin B Isolated From Datura ferox in Zebrafish.Chemistry & biodiversity · 2025Article
- Calmodulin binding is required for calcium mediated TRPA1 desensitization.Nature communications · 2025Article
- Untargeted Diversity-Oriented Synthesis for the Discovery of New Antitumor Agents: An Integrated Approach of Inverse Virtual Screening, Bioinformatics, and Omics for Target Deconvolution.Journal of medicinal chemistry · 2025Article
- Article
- TRPML2 in distinct states reveals the activation and modulation principles of the TRPML family.Nature communications · 2025Article
- Insights into Molecular Interactions and Biological Effect of Natural Stilbenoids at the TRPA1 Ion Channel.ChemMedChem · 2025Article
- Thermo-TRP regulation by endogenous factors and its physiological function at core body temperature.Physiological reports · 2025Review
- Identification and development of TRPM4 antagonists to counteract neuronal excitotoxicity.iScience · 2024Article
- Sea Anemone Kunitz Peptide HCIQ2c1: Structure, Modulation of TRPA1 Channel, and Suppression of Nociceptive Reaction In Vivo.Marine drugs · 2024Article
- The Interaction Mechanism Between C14-Polyacetylene Compounds and the Rat TRPA1 Receptor: An In Silico Study.International journal of molecular sciences · 2024Article
- TRPA1 Inhibition Effects by 3-Phenylcoumarin Derivatives.ACS medicinal chemistry letters · 2024Article
- Design of Novel TRPA1 Agonists Based on Structure of Natural Vasodilator Carvacrol-In Vitro and In Silico Studies.Pharmaceutics · 2024Article
- Structural basis of selective TRPM7 inhibition by the anticancer agent CCT128930.Cell reports · 2024Article
- Human Transient Receptor Potential Ankyrin 1 Channel: Structure, Function, and Physiology.Sub-cellular biochemistry · 2024Review
- Xenobiotic Exposure and Migraine-Associated Signaling: A Multimethod Experimental Study Exploring Cellular Assays in Combination withEnvironmental health perspectives · 2023Article
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Authors and funding
24 authors at 2 institutions in 2 countries.
Funding
Abstract
The TRPA1 ion channel is activated by electrophilic compounds through the covalent modification of intracellular cysteine residues. How non-covalent agonists activate the channel and whether covalent and non-covalent agonists elicit the same physiological responses are not understood. Here, we report the discovery of a non-covalent agonist, GNE551, and determine a cryo-EM structure of the TRPA1-GNE551 complex, revealing a distinct binding pocket and ligand-interaction mechanism. Unlike the covalent agonist allyl isothiocyanate, which elicits channel desensitization, tachyphylaxis, and transient pain, GNE551 activates TRPA1 into a distinct conducting state without desensitization and induces persistent pain. Furthermore, GNE551-evoked pain is relatively insensitive to antagonist treatment. Thus, we demonstrate the biased agonism of TRPA1, a finding that has important implications for the discovery of effective drugs tailored to different disease etiologies.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.