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Structural mechanism of human oncochannel TRPV6 inhibition by the natural phytoestrogen genistein
Calcium-selective oncochannel TRPV6 is the major driver of cell proliferation in human cancers. While significant effort has been invested in the development of synthetic TRPV6 inhibitors, natural channel blockers have been largely neglected. Here we report the structure of human TRPV6 in complex wi...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10169861/ https://www.ncbi.nlm.nih.gov/pubmed/37160865 http://dx.doi.org/10.1038/s41467-023-38352-5 |
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author | Neuberger, Arthur Trofimov, Yury A. Yelshanskaya, Maria V. Nadezhdin, Kirill D. Krylov, Nikolay A. Efremov, Roman G. Sobolevsky, Alexander I. |
author_facet | Neuberger, Arthur Trofimov, Yury A. Yelshanskaya, Maria V. Nadezhdin, Kirill D. Krylov, Nikolay A. Efremov, Roman G. Sobolevsky, Alexander I. |
author_sort | Neuberger, Arthur |
collection | PubMed |
description | Calcium-selective oncochannel TRPV6 is the major driver of cell proliferation in human cancers. While significant effort has been invested in the development of synthetic TRPV6 inhibitors, natural channel blockers have been largely neglected. Here we report the structure of human TRPV6 in complex with the plant-derived phytoestrogen genistein, extracted from Styphnolobium japonicum, that was shown to inhibit cell invasion and metastasis in cancer clinical trials. Despite the pharmacological value, the molecular mechanism of TRPV6 inhibition by genistein has remained enigmatic. We use cryo-EM combined with electrophysiology, calcium imaging, mutagenesis, and molecular dynamics simulations to show that genistein binds in the intracellular half of the TRPV6 pore and acts as an ion channel blocker and gating modifier. Genistein binding to the open channel causes pore closure and a two-fold symmetrical conformational rearrangement in the S4–S5 and S6-TRP helix regions. The unprecedented mechanism of TRPV6 inhibition by genistein uncovers new possibilities in structure-based drug design. |
format | Online Article Text |
id | pubmed-10169861 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-101698612023-05-11 Structural mechanism of human oncochannel TRPV6 inhibition by the natural phytoestrogen genistein Neuberger, Arthur Trofimov, Yury A. Yelshanskaya, Maria V. Nadezhdin, Kirill D. Krylov, Nikolay A. Efremov, Roman G. Sobolevsky, Alexander I. Nat Commun Article Calcium-selective oncochannel TRPV6 is the major driver of cell proliferation in human cancers. While significant effort has been invested in the development of synthetic TRPV6 inhibitors, natural channel blockers have been largely neglected. Here we report the structure of human TRPV6 in complex with the plant-derived phytoestrogen genistein, extracted from Styphnolobium japonicum, that was shown to inhibit cell invasion and metastasis in cancer clinical trials. Despite the pharmacological value, the molecular mechanism of TRPV6 inhibition by genistein has remained enigmatic. We use cryo-EM combined with electrophysiology, calcium imaging, mutagenesis, and molecular dynamics simulations to show that genistein binds in the intracellular half of the TRPV6 pore and acts as an ion channel blocker and gating modifier. Genistein binding to the open channel causes pore closure and a two-fold symmetrical conformational rearrangement in the S4–S5 and S6-TRP helix regions. The unprecedented mechanism of TRPV6 inhibition by genistein uncovers new possibilities in structure-based drug design. Nature Publishing Group UK 2023-05-09 /pmc/articles/PMC10169861/ /pubmed/37160865 http://dx.doi.org/10.1038/s41467-023-38352-5 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Neuberger, Arthur Trofimov, Yury A. Yelshanskaya, Maria V. Nadezhdin, Kirill D. Krylov, Nikolay A. Efremov, Roman G. Sobolevsky, Alexander I. Structural mechanism of human oncochannel TRPV6 inhibition by the natural phytoestrogen genistein |
title | Structural mechanism of human oncochannel TRPV6 inhibition by the natural phytoestrogen genistein |
title_full | Structural mechanism of human oncochannel TRPV6 inhibition by the natural phytoestrogen genistein |
title_fullStr | Structural mechanism of human oncochannel TRPV6 inhibition by the natural phytoestrogen genistein |
title_full_unstemmed | Structural mechanism of human oncochannel TRPV6 inhibition by the natural phytoestrogen genistein |
title_short | Structural mechanism of human oncochannel TRPV6 inhibition by the natural phytoestrogen genistein |
title_sort | structural mechanism of human oncochannel trpv6 inhibition by the natural phytoestrogen genistein |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10169861/ https://www.ncbi.nlm.nih.gov/pubmed/37160865 http://dx.doi.org/10.1038/s41467-023-38352-5 |
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