Structure of human TRPM8 channel.

Abstract

SUMMARYTRPM8 is a calcium ion channel that is activated by multiple factors, such as temperature, voltage, pressure, and osmolality. It is a therapeutic target for anticancer drug development, and its modulators can be utilized for several pathological conditions. Here, we present a cryo-electron microscopy structure of a human TRPM8 channel in the closed state that was solved at 2.7 [A] resolution. Based on our reconstruction, we built the most complete model of the N-terminal pre-melastatin homology region. We also visualized several ligands that are bound by the protein and modeled how the human channel interacts with icilin. Analyses of pore helices showed that all available TRPM8 structures can be grouped into closed and desensitized states based on the register of pore helix S6 and the resulting positioning of particular amino acid residues at the channel constriction.