Structural insights into TRPV2 activation by small molecules

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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.
Funding Information
  • U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (R01GM103899, R01GM129357)
  • U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences
  • NOVA | Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa (SFRH/BPD/143583/2019, IF/00624/2015)
  • Royal Society (URF\R\180019)

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