Human TRPV1 structure and inhibition by the analgesic SB-366791
Published on 04.28.2023 in Nature Communications
Arthur Neuberger, Mai Oda, Yury A. Nikolaev, Kirill D. Nadezhdin, Elena O. Gracheva, Sviatoslav N. Bagriantsev and Alexander I. Sobolevsky
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.
This work was done in collaboration with Dr. E. Gracheva and Dr. S. Bagriantsev
This is an open access article
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