Nature Communications (Apr 2023)

Human TRPV1 structure and inhibition by the analgesic SB-366791

  • Arthur Neuberger,
  • Mai Oda,
  • Yury A. Nikolaev,
  • Kirill D. Nadezhdin,
  • Elena O. Gracheva,
  • Sviatoslav N. Bagriantsev,
  • Alexander I. Sobolevsky

DOI
https://doi.org/10.1038/s41467-023-38162-9
Journal volume & issue
Vol. 14, no. 1
pp. 1 – 10

Abstract

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Abstract Pain therapy has remained conceptually stagnant since the opioid crisis, which highlighted the dangers of treating pain with opioids. An alternative addiction-free strategy to conventional painkiller-based treatment is targeting receptors at the origin of the pain pathway, such as transient receptor potential (TRP) ion channels. Thus, a founding member of the vanilloid subfamily of TRP channels, TRPV1, represents one of the most sought-after pain therapy targets. The need for selective TRPV1 inhibitors extends beyond pain treatment, to other diseases associated with this channel, including psychiatric disorders. Here we report the cryo-electron microscopy structures of human TRPV1 in the apo state and in complex with the TRPV1-specific nanomolar-affinity analgesic antagonist SB-366791. SB-366791 binds to the vanilloid site and acts as an allosteric hTRPV1 inhibitor. SB-366791 binding site is supported by mutagenesis combined with electrophysiological recordings and can be further explored to design new drugs targeting TRPV1 in disease conditions.