Abstract
TRPC1/4/5 channels are non-specific cation channels implicated in a wide variety of diseases, and TRPC1/4/5 inhibitors have recently entered clinical trials. However, fundamental and translational studies require a better understanding of TRPC1/4/5 channel regulation by endogenous and exogenous factors. Although several potent and selective TRPC1/4/5 modulators have been reported, the paucity of mechanistic insights into their modes-of-action remains a barrier to the development of new chemical probes and drug candidates. Xanthine-based modulators include the most potent and selective TRPC1/4/5 inhibitors described to date, as well as TRPC5 activators. Our previous studies suggest that xanthines interact with a, so far, elusive pocket of TRPC1/4/5 channels that is essential to channel gating. Here we report the structure of a small-molecule-bound TRPC1/4/5 channel—human TRPC5 in complex with the xanthine Pico145—to 3.0 Å. We found that Pico145 binds to a conserved lipid binding site of TRPC5, where it displaces a bound phospholipid. Our findings explain the mode-of-action of xanthine-based TRPC1/4/5 modulators, and suggest a structural basis for TRPC1/4/5 modulation by endogenous factors such as (phospho)lipids and Zn2+ ions. These studies lay the foundations for the structure-based design of new generations of TRPC1/4/5 modulators.
Highlights
TRPC1/4/5 channels are non-specific cation channels implicated in a wide variety of diseases, and TRPC1/4/5 inhibitors have recently entered clinical trials
Upon overexpression in HEK 293 cells, TRPC5:C5 channels formed by this construct were activated by englerin A (EA)
IC50 1.8 nM for full-length hTRPC5) (Supplementary Fig. 1). These results suggest maltose-binding protein (MBP)-protease site (PreS)-hTRPC5Δ766–975 as a suitable construct for structural determination of the xanthine-binding site
Summary
TRPC1/4/5 channels are non-specific cation channels implicated in a wide variety of diseases, and TRPC1/4/5 inhibitors have recently entered clinical trials. Our findings explain the mode-of-action of xanthine-based TRPC1/4/5 modulators, and suggest a structural basis for TRPC1/4/5 modulation by endogenous factors such as (phospho)lipids and Zn2+ ions. These studies lay the foundations for the structure-based design of new generations of TRPC1/4/5 modulators. Disruption of the Trpc4/5 genes[16] and global expression of a dominant-negative mutant TRPC512 do not cause catastrophic phenotypes in rodents, TRPC1/4/5 channels have been implicated in a wide range of physiological and pathological mechanisms[4,5,10,17] These findings have driven the development of potent and selective TRPC1/4/5 modulators as chemical probes and drug candidates[5,10,18], and clinical trials have been started by. Hydra Biosciences/Boehringer Ingelheim (the TRPC4/5 channel inhibitor BI 135889 for treatment of anxiety/CNS disorders) and Goldfinch Bio (the TRPC5 channel inhibitor GFB-887 for genetically driven kidney disease)
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