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Figure 3 (A) Close-up of ligand-binding pocket in the apo TRPC4 structure, which is enclosed by the four helices S1 to S4 of the voltage sensing-like domain. (B) Superposition of inhibitor-bound (red) and apo (blue) structure of TRPC4. A close-up of the ligand-binding pocket is shown, with important and interacting residues highlighted. The inhibitor GFB-8438 is depicted in red, positions of the surrounding helices S1 to S4 are indicated. (C) and (D) Same as in (B) for the inhibitor GFB-9289 and GFB-8749 -bound TRPC4 structures respectively. The structures of GFB-9289 and GFB-8749 are depicted in green and cyan respectively. In all the inhibitor-bound structures, several residues move away from the center of the pocket to create space for accommodating the respective ligand. (E) Position of the inhibitor AM-1473 within the VSL domain binding pocket of TRPC6 is shown. The surrounding helices S1-S3 are indicated for orientation. (F) Superposition of GFB-8438-bound TRPC4 (red) and AM-1473-bound TRPC6 (purple) channels. The location of the GFB-8438 inhibitor within the VSL domain is shown. In contrast to AM-1473, which is located in the lower part of the binding pocket (see E), GFB-8438 additionally interacts with the upper region of the pocket. The depicted residues in this region contribute to the selectivity of GFB-8438 for TRP4/5 channels. (G) Comparison of small-molecule modulators of the TRP channel family that target the ligand-binding pocket enclosed by the helices of the VSL domain (VSLD). Small molecules are depicted as space-filled spheres with inhibitors shown in red. Residues interacting with the ligand are shown in stick representation. Pore helices are colored in blue, the TRP helix in orange.