Human TRPV1 structure and inhibition by the analgesic SB-366791.

Autor: Neuberger A; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA., Oda M; Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, 06510, USA., Nikolaev YA; Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, 06510, USA., Nadezhdin KD; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA., Gracheva EO; Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, 06510, USA.; Department of Neuroscience, Yale University School of Medicine, New Haven, CT, 06510, USA.; Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT, 06510, USA.; Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, CT, 06510, USA., Bagriantsev SN; Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, 06510, USA., Sobolevsky AI; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA. as4005@cumc.columbia.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Apr 28; Vol. 14 (1), pp. 2451. Date of Electronic Publication: 2023 Apr 28.
DOI: 10.1038/s41467-023-38162-9
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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