Structural insights into TRPV2 activation by small molecules
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
Yarov-Yarovoy, Vladimir
Leffler, Andreas
Moiseenkova-Bell, Vera Y
Publication Date
2022-04-28Journal Title
Nature Communications
Publisher
Nature Publishing Group UK
Volume
13
Issue
1
Language
en
Type
Article
This Version
VoR
Metadata
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. Nature Communications, 13 (1) https://doi.org/10.1038/s41467-022-30083-3
Description
Funder: U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)
Abstract
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.
Keywords
Article, /631/535/1258/1259, /631/45/269/1153, /9/74, /101/28, article
Sponsorship
U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS) (R01GM103899, R01GM129357)
NOVA | Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa (FCT/UNL) (SFRH/BPD/143583/2019, IF/00624/2015)
Royal Society (URF\R\180019)
Identifiers
s41467-022-30083-3, 30083
External DOI: https://doi.org/10.1038/s41467-022-30083-3
This record's URL: https://www.repository.cam.ac.uk/handle/1810/336573
Rights
Licence:
http://creativecommons.org/licenses/by/4.0/
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