Open Access
Nature Communications, volume 14, issue 1, publication number 4630
Molecular pathway and structural mechanism of human oncochannel TRPV6 inhibition by the phytocannabinoid tetrahydrocannabivarin
Publication type: Journal Article
Publication date: 2023-08-02
Journal:
Nature Communications
Quartile SCImago
Q1
Quartile WOS
Q1
Impact factor: 16.6
ISSN: 20411723
General Chemistry
General Biochemistry, Genetics and Molecular Biology
Multidisciplinary
General Physics and Astronomy
Abstract
The calcium-selective oncochannel TRPV6 is an important driver of cell proliferation in human cancers. Despite increasing interest of pharmacological research in developing synthetic inhibitors of TRPV6, natural compounds acting at this channel have been largely neglected. On the other hand, pharmacokinetics of natural small-molecule antagonists optimized by nature throughout evolution endows these compounds with a medicinal potential to serve as potent and safe next-generation anti-cancer drugs. Here we report the structure of human TRPV6 in complex with tetrahydrocannabivarin (THCV), a natural cannabinoid inhibitor extracted from Cannabis sativa. We use cryo-electron microscopy combined with electrophysiology, calcium imaging, mutagenesis, and molecular dynamics simulations to identify THCV binding sites in the portals that connect the membrane environment surrounding the protein to the central cavity of the channel pore and to characterize the allosteric mechanism of TRPV6 inhibition. We also propose the molecular pathway taken by THCV to reach its binding site. Our study provides a foundation for the development of new TRPV6-targeting drugs.
Citations by journals
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1
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Channels
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Channels
1 publication, 33.33%
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Antioxidants
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Antioxidants
1 publication, 33.33%
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International Journal of Molecular Sciences
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International Journal of Molecular Sciences
1 publication, 33.33%
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1
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Citations by publishers
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1
2
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Multidisciplinary Digital Publishing Institute (MDPI)
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Multidisciplinary Digital Publishing Institute (MDPI)
2 publications, 66.67%
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Taylor & Francis
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Taylor & Francis
1 publication, 33.33%
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1
2
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- We do not take into account publications that without a DOI.
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- Statistics recalculated weekly.
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Neuberger A. et al. Molecular pathway and structural mechanism of human oncochannel TRPV6 inhibition by the phytocannabinoid tetrahydrocannabivarin // Nature Communications. 2023. Vol. 14. No. 1. 4630
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Neuberger A., Trofimov Y. A., Yelshanskaya M. V., Khau J., Nadezhdin K. D., Khosrof L. S., Krylov N. A., Efremov R. G., Sobolevsky A. I. Molecular pathway and structural mechanism of human oncochannel TRPV6 inhibition by the phytocannabinoid tetrahydrocannabivarin // Nature Communications. 2023. Vol. 14. No. 1. 4630
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TY - JOUR
DO - 10.1038/s41467-023-40362-2
UR - https://doi.org/10.1038%2Fs41467-023-40362-2
TI - Molecular pathway and structural mechanism of human oncochannel TRPV6 inhibition by the phytocannabinoid tetrahydrocannabivarin
T2 - Nature Communications
AU - Neuberger, A.
AU - Trofimov, Yury A
AU - Yelshanskaya, Maria V
AU - Khau, Jeffrey
AU - Nadezhdin, Kirill D
AU - Khosrof, Lena S.
AU - Krylov, Nikolay A
AU - Efremov, Roman G
AU - Sobolevsky, Alexander I.
PY - 2023
DA - 2023/08/02 00:00:00
PB - Springer Nature
IS - 1
VL - 14
SN - 2041-1723
ER -
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@article{2023_Neuberger,
author = {A. Neuberger and Yury A Trofimov and Maria V Yelshanskaya and Jeffrey Khau and Kirill D Nadezhdin and Lena S. Khosrof and Nikolay A Krylov and Roman G Efremov and Alexander I. Sobolevsky},
title = {Molecular pathway and structural mechanism of human oncochannel TRPV6 inhibition by the phytocannabinoid tetrahydrocannabivarin},
journal = {Nature Communications},
year = {2023},
volume = {14},
publisher = {Springer Nature},
month = {aug},
url = {https://doi.org/10.1038%2Fs41467-023-40362-2},
number = {1},
doi = {10.1038/s41467-023-40362-2}
}