دورية أكاديمية
Structural insights into TRPV2 activation by small molecules
| العنوان: | Structural insights into TRPV2 activation by small molecules |
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| المؤلفون: | Pumroy, Ruth A., Protopopova, Anna D., Fricke, Tabea C., Lange, Iris U., Haug, Ferdinand M., Nguyen, Phuong T., Gallo, Pamela N., Sousa, Bárbara B., Bernardes, Gonçalo J. L., Yarov-Yarovoy, Vladimir, Leffler, Andreas, Moiseenkova-Bell, Vera Y. |
| المساهمون: | Repositório da Universidade de Lisboa |
| بيانات النشر: | Springer Nature, 2022. |
| سنة النشر: | 2022 |
| الوصف: | © The Author(s) 2022. 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/4.0Test/. |
| الوصف (مترجم): | Transient receptor potential vanilloid 2 (TRPV2) is involved in many critical physiological and pathophysiological processes, making it a promising drug target. Here we present cryo-electron microscopy (cryo-EM) structures of rat TRPV2 in lipid nanodiscs activated by 2-aminoethoxydiphenyl borate (2-APB) and propose a TRPV2-specific 2-ABP binding site at the interface of S5 of one monomer and the S4-S5 linker of the adjacent monomer. In silico docking and electrophysiological studies confirm the key role of His521 and Arg539 in 2-APB activation of TRPV2. Additionally, electrophysiological experiments show that the combination of 2-APB and cannabidiol has a synergetic effect on TRPV2 activation, and cryo-EM structures demonstrate that both drugs were able to bind simultaneously. Together, our cryo-EM structures represent multiple functional states of the channel, providing a native picture of TRPV2 activation by small molecules and a structural framework for the development of TRPV2-specific activators. This work was supported by grants from the National Institute of Health (R01GM103899 and R01GM129357 to V.Y.M.-B.), from the Royal Society (URF\R\180019 to G.J.L.B.), from FCT Portugal (FCT Investigator, IF/00624/2015 to G.J.L.B., SFRH/BPD/143583/2019 to B.B.S.). |
| نوع الوثيقة: | journal article |
| وصف الملف: | application/pdf |
| اللغة: | English |
| العلاقة: | Nat Commun. 2022 Apr 28;13(1):2334; 2041-1723 |
| DOI: | 10.1038/s41467-022-30083-3 |
| الإتاحة: | http://hdl.handle.net/10451/52650Test |
| حقوق: | open access |
| رقم الانضمام: | rcaap.com.ul.repositorio.ul.pt.10451.52650 |
| قاعدة البيانات: | RCAAP |
| DOI: | 10.1038/s41467-022-30083-3 |
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