8G1A

Cryo-EM structure of Nav1.7 with CBD

Summary for 8G1A

• Entry DOI: 10.2210/pdb8g1a/pdb
• EMDB information: 29665
• Descriptor: Sodium channel protein type 9 subunit alpha, 1-O-OCTADECYL-SN-GLYCERO-3-PHOSPHOCHOLINE, 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE, ... (11 entities in total)
• Functional Keywords: cryo-em, sodium channel, vgsc, nav1.7, cbd, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 292863.27

Authors

Fan, X.,Huang, J.,Yan, N. (deposition date: 2023-02-01, release date: 2023-07-05, Last modification date: 2025-05-14)

Primary citation

Huang, J.,Fan, X.,Jin, X.,Jo, S.,Zhang, H.B.,Fujita, A.,Bean, B.P.,Yan, N.
Cannabidiol inhibits Na v channels through two distinct binding sites.
Nat Commun, 14:3613-3613, 2023

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 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.

PubMed: 37330538
DOI: 10.1038/s41467-023-39307-6

Experimental method

ELECTRON MICROSCOPY (2.8 Å)