Structural basis for pharmacological modulation of the TRPC6 channel

Area of Science:

• Biochemistry
• Structural Biology
• Molecular Physiology

Background:

• Transient receptor potential canonical (TRPC) proteins, including TRPC6, are nonselective cation channels crucial for cellular functions.
• TRPC6 inhibition shows therapeutic promise for cardiac and renal diseases, yet its precise function and modulation mechanisms require further elucidation.

Purpose of the Study:

• To determine the cryo-electron microscopy (cryo-EM) structures of TRPC6 in antagonist- and agonist-bound states.
• To elucidate the molecular mechanisms underlying TRPC6 modulation by small-molecule ligands.
• To investigate the structural basis of disease-related mutations in TRPC6.

Main Methods:

• Cryo-electron microscopy (cryo-EM) to resolve TRPC6 structures.
• Mutagenesis studies to validate ligand binding sites and functional effects.
• Structural analysis to understand conformational changes upon ligand binding.

Main Results:

• Novel antagonist and agonist binding sites on TRPC6 were identified through cryo-EM structures.
• Antagonist binds to a cytoplasm-facing pocket (S1-S4, TRP helix), while the agonist binds at the subunit interface (S6, pore helix).
• Disease-associated mutations were found to enhance TRPC6 activity by disrupting interfacial interactions.

Conclusions:

• The study provides high-resolution structures of TRPC6, revealing key sites for small-molecule modulator interaction.
• Conformational changes upon ligand binding offer mechanistic insights into TRPC6 channel regulation.
• Findings facilitate the rational design of TRPC6-targeted therapeutics for TRPC6-mediated pathologies.