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Title | Cannabidiol inhibits Na channels through two distinct binding sites. |
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Journal, issue, pages | Nat Commun, Vol. 14, Issue 1, Page 3613, Year 2023 |
Publish date | Jun 17, 2023 |
Authors | Jian Huang / Xiao Fan / Xueqin Jin / Sooyeon Jo / Hanxiong Bear Zhang / Akie Fujita / Bruce P Bean / Nieng Yan / |
PubMed Abstract | Cannabidiol (CBD), a major non-psychoactive phytocannabinoid in cannabis, is an effective treatment for some forms of epilepsy and pain. At high concentrations, CBD interacts with a huge variety of ...Cannabidiol (CBD), a major non-psychoactive phytocannabinoid in cannabis, is an effective treatment for some forms of epilepsy and pain. At high concentrations, CBD interacts with a huge variety of proteins, but which targets are most relevant for clinical actions is still unclear. Here we show that CBD interacts with Na1.7 channels at sub-micromolar concentrations in a state-dependent manner. Electrophysiological experiments show that CBD binds to the inactivated state of Na1.7 channels with a dissociation constant of about 50 nM. The cryo-EM structure of CBD bound to Na1.7 channels reveals two distinct binding sites. One is in the IV-I fenestration near the upper pore. The other binding site is directly next to the inactivated "wedged" position of the Ile/Phe/Met (IFM) motif on the short linker between repeats III and IV, which mediates fast inactivation. Consistent with producing a direct stabilization of the inactivated state, mutating residues in this binding site greatly reduced state-dependent binding of CBD. The identification of this binding site may enable design of compounds with improved properties compared to CBD itself. |
External links | Nat Commun / PubMed:37330538 / PubMed Central |
Methods | EM (single particle) |
Resolution | 2.8 Å |
Structure data | EMDB-29665, PDB-8g1a: |
Chemicals | ChemComp-NAG: ChemComp-P0T: ChemComp-P5S: ChemComp-Y01: ChemComp-9Z9: ChemComp-LPE: ChemComp-PCW: |
Source |
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Keywords | MEMBRANE PROTEIN / Cryo-EM / sodium channel / VGSC / Nav1.7 / CBD |