Molecular pathway and structural mechanism of human oncochannel TRPV6 inhibition by the phytocannabinoid tetrahydrocannabivarin
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...
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| Format: | Article |
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Nature Portfolio
2023-08-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-40362-2 |
| _version_ | 1797752677168316416 |
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| author | Arthur Neuberger Yury A. Trofimov Maria V. Yelshanskaya Jeffrey Khau Kirill D. Nadezhdin Lena S. Khosrof Nikolay A. Krylov Roman G. Efremov Alexander I. Sobolevsky |
| author_facet | Arthur Neuberger Yury A. Trofimov Maria V. Yelshanskaya Jeffrey Khau Kirill D. Nadezhdin Lena S. Khosrof Nikolay A. Krylov Roman G. Efremov Alexander I. Sobolevsky |
| author_sort | Arthur Neuberger |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T17:06:50Z |
| format | Article |
| id | doaj.art-24770a8288e94d4a9af6eb8f2702c528 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-12T17:06:50Z |
| publishDate | 2023-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-24770a8288e94d4a9af6eb8f2702c5282023-08-06T11:19:55ZengNature PortfolioNature Communications2041-17232023-08-0114111310.1038/s41467-023-40362-2Molecular pathway and structural mechanism of human oncochannel TRPV6 inhibition by the phytocannabinoid tetrahydrocannabivarinArthur Neuberger0Yury A. Trofimov1Maria V. Yelshanskaya2Jeffrey Khau3Kirill D. Nadezhdin4Lena S. Khosrof5Nikolay A. Krylov6Roman G. Efremov7Alexander I. Sobolevsky8Department of Biochemistry and Molecular Biophysics, Columbia UniversityShemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of SciencesDepartment of Biochemistry and Molecular Biophysics, Columbia UniversityDepartment of Biochemistry and Molecular Biophysics, Columbia UniversityDepartment of Biochemistry and Molecular Biophysics, Columbia UniversityDepartment of Biochemistry and Molecular Biophysics, Columbia UniversityShemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of SciencesShemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of SciencesDepartment of Biochemistry and Molecular Biophysics, Columbia UniversityAbstract 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.https://doi.org/10.1038/s41467-023-40362-2 |
| spellingShingle | Arthur Neuberger Yury A. Trofimov Maria V. Yelshanskaya Jeffrey Khau Kirill D. Nadezhdin Lena S. Khosrof Nikolay A. Krylov Roman G. Efremov Alexander I. Sobolevsky Molecular pathway and structural mechanism of human oncochannel TRPV6 inhibition by the phytocannabinoid tetrahydrocannabivarin Nature Communications |
| title | Molecular pathway and structural mechanism of human oncochannel TRPV6 inhibition by the phytocannabinoid tetrahydrocannabivarin |
| title_full | Molecular pathway and structural mechanism of human oncochannel TRPV6 inhibition by the phytocannabinoid tetrahydrocannabivarin |
| title_fullStr | Molecular pathway and structural mechanism of human oncochannel TRPV6 inhibition by the phytocannabinoid tetrahydrocannabivarin |
| title_full_unstemmed | Molecular pathway and structural mechanism of human oncochannel TRPV6 inhibition by the phytocannabinoid tetrahydrocannabivarin |
| title_short | Molecular pathway and structural mechanism of human oncochannel TRPV6 inhibition by the phytocannabinoid tetrahydrocannabivarin |
| title_sort | molecular pathway and structural mechanism of human oncochannel trpv6 inhibition by the phytocannabinoid tetrahydrocannabivarin |
| url | https://doi.org/10.1038/s41467-023-40362-2 |
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