Structural insights into TRPV2 activation by small molecules.
View / Open Files
Authors
Pumroy, Ruth A
Protopopova, Anna D
Fricke, Tabea C
Lange, Iris U
Haug, Ferdinand M
Nguyen, Phuong T
Gallo, Pamela N
Sousa, Bárbara B
Leffler, Andreas
Publication Date
2022-04-28Journal Title
Nat Commun
ISSN
2041-1723
Publisher
Springer Science and Business Media LLC
Type
Article
This Version
AM
Later Version(s)
https://www.repository.cam.ac.uk/handle/1810/337725Metadata
Show full item recordCitation
Pumroy, R. A., Protopopova, A. D., Fricke, T. C., Lange, I. U., Haug, F. M., Nguyen, P. T., Gallo, P. N., et al. (2022). Structural insights into TRPV2 activation by small molecules.. Nat Commun https://doi.org/10.1038/s41467-022-30083-3
Abstract
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.
Sponsorship
Royal Society (URF\R\180019)
Embargo Lift Date
2100-01-01
Identifiers
External DOI: https://doi.org/10.1038/s41467-022-30083-3
This record's URL: https://www.repository.cam.ac.uk/handle/1810/336356
Statistics
Total file downloads (since January 2020). For more information on metrics see the
IRUS guide.
Recommended or similar items
The current recommendation prototype on the Apollo Repository will be turned off on 03 February 2023. Although the pilot has been fruitful for both parties, the service provider IKVA is focusing on horizon scanning products and so the recommender service can no longer be supported. We recognise the importance of recommender services in supporting research discovery and are evaluating offerings from other service providers. If you would like to offer feedback on this decision please contact us on: support@repository.cam.ac.uk