Figure 3. Comparison of the ligand-binding pocket in TRPC4.
(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.
Figure 3—figure supplement 1. Sequence alignment of zebrafish TRPC4, human TRPC4, TRPC5, and TRPC6.
