Structural insights into TRPM8 inhibition and desensitization

Responding to the cold Mint tastes cool because the active component, menthol, activates the receptor and calcium channel TRPM8, which also responds to cold temperatures. Previous structures have revealed the architecture of TRPM8 and how it binds ligands but not its gating mechanism. Diver et al. determined structures of avian TRPM8 in ligand-free, antagonist-bound, and calcium-bound states using cryo–electron microscopy at resolutions between 3.0 and 3.6 angstroms. They observed a closed state in the presence of antagonist and that large conformational changes are required to form the desensitized state in the presence of calcium. Understanding how ligands affect channel gating may facilitate drug design. Science , this issue p. 1434