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Structure paper

TitleMolecular mechanism of TRPV2 channel modulation by cannabidiol.
Journal, issue, pagesElife, Vol. 8, Year 2019
Publish dateSep 30, 2019
AuthorsRuth A Pumroy / Amrita Samanta / Yuhang Liu / Taylor Et Hughes / Siyuan Zhao / Yevgen Yudin / Tibor Rohacs / Seungil Han / Vera Y Moiseenkova-Bell /
PubMed AbstractTransient receptor potential vanilloid 2 (TRPV2) plays a critical role in neuronal development, cardiac function, immunity, and cancer. Cannabidiol (CBD), the non-psychotropic therapeutically active ...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 , 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.
External linksElife / PubMed:31566564 / PubMed Central
MethodsEM (single particle)
Resolution3.2 - 4.0 Å
Structure data

20677

6u84

EMDB-20677, PDB-6u84:
Apo full-length rat TRPV2 in nanodiscs, state 1
Method: EM (single particle) / Resolution: 3.7 Å

20678

6u86

EMDB-20678, PDB-6u86:
Apo full-length rat TRPV2 in nanodiscs, state 2
Method: EM (single particle) / Resolution: 4.0 Å

20682

6u88

EMDB-20682, PDB-6u88:
CBD-bound full-length rat TRPV2 in nanodiscs, state 2
Method: EM (single particle) / Resolution: 3.2 Å

20686

6u8a

EMDB-20686, PDB-6u8a:
CBD-bound full-length rat TRPV2 in nanodiscs, state 1
Method: EM (single particle) / Resolution: 3.4 Å

Chemicals

ChemComp-P0T:
cannabidiol

Source
  • rattus norvegicus (Norway rat)
KeywordsTRANSPORT PROTEIN / ion channel / TRPV2 / TRP channel / cannabidiol

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