Molecular mechanism of TRPV2 channel modulation by cannabidiol
- University of Pennsylvania, United States
- Pfizer Research and Development, United States
- New Jersey Medical School, Rutgers, the State University of New Jersey, United States
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.
Data availability
cryoEM maps have been deposited in the Electron Microscopy Data Bank under the following accession codes: EMD-20677, EMD-20678, EMD-20686, EMD-20682The models built into the cryoEM maps have been deposited into the Protein Data Bank under the following accession codes: 6U84, 6U85, 6U8A, 6U88The maps and models analyzed in this study are included with the manuscript and supporting files.
-
Apo full-length rat TRPV2 in nanodiscs, state 1Electron Microscopy Data Bank, EMD-20677.
-
Apo full-length rat TRPV2 in nanodiscs, state 1Protein Data Bank, PDB 6U84.
-
Apo full-length rat TRPV2 in nanodiscs, state 2Electron Microscopy Data Bank, EMD-20678.
-
Apo full-length rat TRPV2 in nanodiscs, state 2Protein Data Bank, PDB 6U86.
-
CBD-bound full-length rat TRPV2 in nanodiscs, state 1Electron Microscopy Data Bank, EMD-20686.
-
CBD-bound full-length rat TRPV2 in nanodiscs, state 1Protein Data Bank, PDB 6U8A.
-
CBD-bound full-length rat TRPV2 in nanodiscs, state 2Electron Microscopy Data Bank, EMD-20682.
-
CBD-bound full-length rat TRPV2 in nanodiscs, state 2Protein Data Bank, PDB 6U88.
Article and author information
Author details
Vera Y Moiseenkova-Bell
Funding
National Institutes of Health (R01GM129357)
- Vera Y Moiseenkova-Bell
National Institutes of Health (R01GM103899)
- Vera Y Moiseenkova-Bell
National Institutes of Health (R01 NS055159)
- Tibor Rohacs
National Institutes of Health (R01GM093290)
- Tibor Rohacs
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2019, Pumroy et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 6,273
- views
-
- 988
- downloads
-
- 117
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Molecular mechanism of TRPV2 channel modulation by cannabidiol
eLife 8:e48792.
https://doi.org/10.7554/eLife.48792
Further reading
-
- Immunology and Inflammation
- Structural Biology and Molecular Biophysics
A potent class of HIV-1 broadly neutralizing antibodies (bnAbs) targets the envelope glycoprotein’s membrane proximal exposed region (MPER) through a proposed mechanism where hypervariable loops embed into lipid bilayers and engage headgroup moieties alongside the epitope. We address the feasibility and determinant molecular features of this mechanism using multi-scale modeling. All-atom simulations of 4E10, PGZL1, 10E8, and LN01 docked onto HIV-like membranes consistently form phospholipid complexes at key complementarity-determining region loop sites, solidifying that stable and specific lipid interactions anchor bnAbs to membrane surfaces. Ancillary protein-lipid contacts reveal surprising contributions from antibody framework regions. Coarse-grained simulations effectively capture antibodies embedding into membranes. Simulations estimating protein-membrane interaction strength for PGZL1 variants along an inferred maturation pathway show bilayer affinity is evolved and correlates with neutralization potency. The modeling demonstrated here uncovers insights into lipid participation in antibodies’ recognition of membrane proteins and highlights antibody features to prioritize in vaccine design.
-
- Plant Biology
- Structural Biology and Molecular Biophysics
The Calvin-Benson-Bassham cycle (CBBC) performs carbon fixation in photosynthetic organisms. Among the eleven enzymes that participate in the pathway, sedoheptulose-1,7-bisphosphatase (SBPase) is expressed in photo-autotrophs and catalyzes the hydrolysis of sedoheptulose-1,7-bisphosphate (SBP) to sedoheptulose-7-phosphate (S7P). SBPase, along with nine other enzymes in the CBBC, contributes to the regeneration of ribulose-1,5-bisphosphate, the carbon-fixing co-substrate used by ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco). The metabolic role of SBPase is restricted to the CBBC, and a recent study revealed that the three-dimensional structure of SBPase from the moss Physcomitrium patens was found to be similar to that of fructose-1,6-bisphosphatase (FBPase), an enzyme involved in both CBBC and neoglucogenesis. In this study we report the first structure of an SBPase from a chlorophyte, the model unicellular green microalga Chlamydomonas reinhardtii. By combining experimental and computational structural analyses, we describe the topology, conformations, and quaternary structure of Chlamydomonas reinhardtii SBPase (CrSBPase). We identify active site residues and locate sites of redox- and phospho-post-translational modifications that contribute to enzymatic functions. Finally, we observe that CrSBPase adopts distinct oligomeric states that may dynamically contribute to the control of its activity.
