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Structural insights into TRPV2 activation by small molecules

Published version
Peer-reviewed

Type

Article

Change log

Authors

Lopes Bernardes, Goncalo  ORCID logo  https://orcid.org/0000-0001-6594-8917
pumroy, ruth 
Protopopova, Anna 
Fricke, Tabea 
Lange, Iris 

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.

Description

Keywords

Animals, Binding Sites, Cryoelectron Microscopy, Protein Domains, Rats, TRPV Cation Channels

Journal Title

Nature Communications

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

13

Publisher

Nature Research
Sponsorship
Royal Society (URF\R\180019)