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Title | A Non-covalent Ligand Reveals Biased Agonism of the TRPA1 Ion Channel. |
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Journal, issue, pages | Neuron, Vol. 109, Issue 2, Page 273-284.e4, Year 2021 |
Publish date | Jan 20, 2021 |
Authors | Chang Liu / Rebecca Reese / Simon Vu / Lionel Rougé / Shannon D Shields / Satoko Kakiuchi-Kiyota / Huifen Chen / Kevin Johnson / Yu Patrick Shi / Tania Chernov-Rogan / Demi Maria Zabala Greiner / Pawan Bir Kohli / David Hackos / Bobby Brillantes / Christine Tam / Tianbo Li / Jianyong Wang / Brian Safina / Steve Magnuson / Matthew Volgraf / Jian Payandeh / Jie Zheng / Alexis Rohou / Jun Chen / |
PubMed 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 ...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. |
External links | Neuron / PubMed:33152265 / PubMed Central |
Methods | EM (single particle) |
Resolution | 3.0 Å |
Structure data | EMDB-22009, PDB-6x2j: |
Chemicals | ChemComp-ULJ: |
Source |
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Keywords | MEMBRANE PROTEIN/Agonist / TRPA1 / channel / agonist / MEMBRANE PROTEIN / MEMBRANE PROTEIN-Agonist complex |