Human TRPC5 structures reveal interaction of a xanthine-based TRPC1/4/5 inhibitor with a conserved lipid binding site
David J Wright1,2, Katie J Simmons1,2, Rachel M Johnson2,3
1Discovery and Translational Science Department, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, LS2 9JT, UK.
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.
Insights
Researchers elucidated the structure of TRPC1/4/5 channels, revealing how xanthine-based modulators bind to a lipid site. This finding explains their mechanism of action and guides the design of new TRPC1/4/5 channel drugs.
Area of Science:
- Biophysics
- Molecular Biology
- Pharmacology
Background:
- TRPC1/4/5 channels are crucial non-specific cation channels involved in numerous diseases.
- TRPC1/4/5 inhibitors are progressing in clinical trials, necessitating a deeper understanding of channel regulation.
- Current knowledge of TRPC1/4/5 modulator mechanisms of action is limited, hindering drug development.
Purpose of the Study:
- To determine the structure of TRPC1/4/5 channels bound to a xanthine modulator.
- To elucidate the mechanism of action for xanthine-based TRPC1/4/5 modulators.
- To provide a structural basis for TRPC1/4/5 channel modulation by endogenous factors.
Main Methods:
- X-ray crystallography was used to determine the structure of human TRPC5 in complex with the xanthine Pico145 at 3.0 Å resolution.
- Structural analysis focused on identifying the binding site and interactions of Pico145 within the TRPC5 channel.
Main Results:
- The structure revealed that Pico145 binds to a conserved lipid-binding site on TRPC5.
- Pico145 was observed to displace a bound phospholipid in the identified binding pocket.
- The binding mode explains the inhibitory and activating effects of xanthine-based modulators on TRPC1/4/5 channels.
Conclusions:
- The study provides the first structural insights into how xanthine-based molecules modulate TRPC1/4/5 channels.
- The findings reveal a conserved lipid-binding site crucial for channel gating and modulation.
- This structural understanding facilitates the rational design of novel TRPC1/4/5 modulators for therapeutic applications.
