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Structural characterization of TRPA1 ion channel in complex with selective agonists


EMSL Project ID
50672

Abstract

Our aim is to determine the structures of agonists bound to TRPA1, a ligand-gated ion channel and polymodal receptor implicated in pain, itch and respiratory diseases.

Electrophilic agonists, such as allyl isothiocyanate, activate TRPA1 through covalent modification of cysteine residues localized in the N-terminus of the channel, but little is known of how covalent modification leads to channel opening, and even less of how non-reactive agonists activate TRPA1. We have discovered novel TRPA1 agonists and identified their putative binding sites using a mutagenesis approach. Structures will generate molecular details on ligand binding and channel gating, thereby providing unprecedented insights into some of the many ways TRPA1 can be activated. This may in turn illuminate the gating and regulation mechanisms of TRPA1 and facilitate future research into understanding TRPA1’s physiological role in health and disease.

Project Details

Start Date
2019-02-04
End Date
2021-03-17
Status
Closed

Team

Principal Investigator

Alexis Rohou
Institution
Genentech, Inc.

Team Members

Craig Yoshioka
Institution
Oregon Health & Science University

Related Publications

Liu, C., Reese, R., Vu, S., Rougé, L., Shields, S., Kakiuchi-Kiyota, S., Chen, H., Johnson, K., Shi, Y., Chernov-Rogan, T., Greiner, D., Kohli, P., Hackos, D., Brillantes, B., Tam, C., Li, T., Wang, J., Safina, B., Magnuson, S., Volgraf, M., Payandeh, J., Zheng, J., Rohou, A., Chen, J. (2020). A Non-covalent Ligand Reveals Biased Agonism of the TRPA1 Ion Channel Neuron https://dx.doi.org/10.1016/j.neuron.2020.10.014