A Non-covalent Ligand Reveals Biased Agonism of the TRPA1 Ion Channel

Neuron. 2021 Jan 20;109(2):273-284.e4. doi: 10.1016/j.neuron.2020.10.014. Epub 2020 Nov 4.

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.

Keywords: TRPA1; biased agonism; covalent; cryo-EM; drug discovery; ion channel; non-covalent; pain.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Female
  • HEK293 Cells
  • Humans
  • Ligands
  • Male
  • Pain Measurement / drug effects
  • Pain Measurement / methods*
  • Protein Structure, Secondary
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Transgenic
  • TRPA1 Cation Channel / agonists*
  • TRPA1 Cation Channel / chemistry
  • TRPA1 Cation Channel / metabolism*

Substances

  • Ligands
  • TRPA1 Cation Channel
  • Trpa1 protein, rat