Structural insights into TRPV2 activation by small molecules

Ruth A. Pumroy, Anna D. Protopopova, Tabea C. Fricke, Iris U. Lange, Ferdinand M. Haug, Phuong T. Nguyen, Pamela N. Gallo, Bárbara B. Sousa, Gonçalo J. L. Bernardes, Vladimir Yarov-Yarovoy, Andreas Leffler and Vera Y. Moiseenkova-Bell ()
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Ruth A. Pumroy: University of Pennsylvania
Anna D. Protopopova: University of Pennsylvania
Tabea C. Fricke: Hannover Medical School
Iris U. Lange: Hannover Medical School
Ferdinand M. Haug: Hannover Medical School
Phuong T. Nguyen: University of California
Pamela N. Gallo: University of Pennsylvania
Bárbara B. Sousa: Universidade de Lisboa
Gonçalo J. L. Bernardes: Universidade de Lisboa
Vladimir Yarov-Yarovoy: University of California
Andreas Leffler: Hannover Medical School
Vera Y. Moiseenkova-Bell: University of Pennsylvania

Nature Communications, 2022, vol. 13, issue 1, 1-12

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.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30083-3

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DOI: 10.1038/s41467-022-30083-3

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