Structure of human TRPM8 channel

TRPM8 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 Å resolution. Our structure comprises 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 in available TRPM structures showed that all these structures can be grouped into different closed, desensitized and open state conformations based on the register of the pore helix S6 which positions particular amino acid residues at the channel constriction. Our structure is the first for the human TRPM8 protein and it is among the most complete and the highest resolution structures of any TRPM8 channel available.