In:
eLife, eLife Sciences Publications, Ltd, Vol. 8 ( 2019-09-30)
Abstract:
Transient receptor potential vanilloid 2 (TRPV2) plays a critical role in neuronal development, cardiac function, immunity, and cancer. Cannabidiol (CBD), the non-psychotropic therapeutically active ingredient of Cannabis sativa, is an activator of TRPV2 and also modulates other transient receptor potential (TRP) channels. Here, we determined structures of the full-length rat TRPV2 channel in apo and CBD-bound states in nanodiscs by cryo-electron microscopy. We show that CBD interacts with TRPV2 through a hydrophobic pocket located between S5 and S6 helices of adjacent subunits, which differs from known ligand and lipid binding sites in other TRP channels. CBD-bound TRPV2 structures revealed that the S4-S5 linker plays a critical role in channel gating upon CBD binding. Additionally, nanodiscs permitted us to visualize two distinct TRPV2 apo states in a lipid environment. Together these results provide a foundation to further understand TRPV channel gating, their divergent physiological functions, and to accelerate structure-based drug design.
Type of Medium:
Online Resource
ISSN:
2050-084X
DOI:
10.7554/eLife.48792.001
DOI:
10.7554/eLife.48792.002
DOI:
10.7554/eLife.48792.003
DOI:
10.7554/eLife.48792.004
DOI:
10.7554/eLife.48792.005
DOI:
10.7554/eLife.48792.006
DOI:
10.7554/eLife.48792.007
DOI:
10.7554/eLife.48792.008
DOI:
10.7554/eLife.48792.009
DOI:
10.7554/eLife.48792.010
DOI:
10.7554/eLife.48792.011
DOI:
10.7554/eLife.48792.012
DOI:
10.7554/eLife.48792.013
DOI:
10.7554/eLife.48792.014
DOI:
10.7554/eLife.48792.015
DOI:
10.7554/eLife.48792.016
DOI:
10.7554/eLife.48792.017
DOI:
10.7554/eLife.48792.018
DOI:
10.7554/eLife.48792.019
DOI:
10.7554/eLife.48792.020
DOI:
10.7554/eLife.48792.021
DOI:
10.7554/eLife.48792.022
DOI:
10.7554/eLife.48792.023
DOI:
10.7554/eLife.48792.024
DOI:
10.7554/eLife.48792.025
DOI:
10.7554/eLife.48792.026
DOI:
10.7554/eLife.48792.044
DOI:
10.7554/eLife.48792.045
Language:
English
Publisher:
eLife Sciences Publications, Ltd
Publication Date:
2019
detail.hit.zdb_id:
2687154-3