Abstract
Transient receptor potential vanilloid 2 (TRPV2) is involved in many physiological and pathophysiological processes, putting TRPV2 on the list of important drug targets. Yet, specific TRPV2 modulators are currently unavailable. Their development requires structural information about TRPV2 interactions with the currently known non-specific TRPV2 agonists and antagonists. Here we present rat TRPV2 structures resolved by cryo-electron microscopy in the presence of 2-aminoethoxydiphenyl borate (2-ABP), 2-APB with doxorubicin, and ruthenium red in lipid membranes. We identified a novel and TRPV2-specific 2-APB binding site between the S5 helix and S4-S5 linker on two adjacent TRPV2 monomers. We identified a ruthenium red binding site at the selectivity filter between the bottom of the pore helix and the pore loop of the same monomer, which is conceivably conserved between TRPV1-4 channels. We also showed that a large organic molecule like doxorubicin can enter the TRPV2 pore in the presence of 2-APB, which is consistent with previous observations using cell-based assays for TRPV2 and other TRP channels. Finally, we discovered a structural lipid bound in a unique position in the “vanilloid pocket”, which is absent in the 2-APB-bound state of the channel, allowing us to propose a model for lipid-dependent TRPV2 channel gating. Together, our results provide a further understanding of TRPV2 opening and a structural framework for the development of TRPV2-specific modulators.
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