(A) Side view of the transmembrane domain of the 2-APB-bound, open structure of mouse TRPV3-Y564A channel (PDB: 6DVZ) (Singh et al., 2018). Adjacent subunits are colored white or dark-grey for contrast. The two 2-APB molecules per subunit assigned to non-protein densities in the transmembrane domain are shown as sticks in orange, with the third 2-APB molecule below the transmembrane domain not shown. Residues that enabled responses to RTx when mutated in TRPV3-6M are shown in sticks for the two subunits at the front, colored either in dark-blue (dark-grey subunit) or lighter blue (white subunit). Residues that did not affect responses to RTx when mutated are shown either in magenta (dark-grey subunit, with labels) or pink (white subunit). Residue labels for F666 and L639, which face the ion-conduction pathway, are shown in black. (B) Structural changes in mouse and human TRPV3 at a protein/membrane interface facing the RTx-binding site. Structures for apo mouse TRPV3 (dark blue, PDB: 6DVW), 2-APB-bound, open mouse TRPV3-Y564A (white, PDB: 6DVZ) (Singh et al., 2018), apo human TRPV3 (yellow, PDB: 6MHO) and 2-APB-sensitized human TRPV3 (pink, PDB: 6MHS) (Zubcevic et al., 2018a) were superimposed using the cealing function in Pymol. Residues and transmembrane helices from one of the two adjacent subunits depicted in the figure are denoted by an apostrophe. Residues that when mutated enabled RTx responses in TRPV3-6M and that are facing that interface are shown in stick representation. (C) Lipids assigned to non-protein densities at the same interface as in (B) shown as orange sticks for the structures of apo TRPV1 (top panel, PDB: 5IRZ) and RTx/DkTx-bound TRPV1 (bottom panel, PDB: 5IRX) in nanodiscs (Gao et al., 2016). Equivalent residues to those that enabled responses to RTx when mutated in TRPV3-6M are shown as sticks in light-blue, and RTx in dark-blue. The labels for the two adjacent subunits depicted are differentiated by an apostrophe. (D) Conformational changes in the pore of mouse TRPV3 as a result of activation by 2-APB (Singh et al., 2018). The pore domains of two opposite subunits are depicted, with the S4-S5 linker of a third subunit shown for reference. Residues in the S6 helices, selectivity filter and pore helices that enabled RTx activation are shown in blue, and those without effect in pink. The side-chain of N671 is also shown to highlight the change in the pore-facing residues in S6 as a result of the α to π transition from the apo (PDB: 6DVW) to the 2-APB-activated state (PDB: 6DVZ).