LAUSR

Significance Ion channels are pore-forming proteins spanning biological membranes. Transient receptor potential ion channels are a subclass of ion channel proteins, characterized by nonselective permeability to cations such as sodium, calcium, magnesium, and zinc, and little voltage sensitivity; their gating is still an area of active investigation. TRPM6 and TRPM7 are ubiquitously expressed with prominent roles in early embryonic development. Uniquely, these channels also include an active kinase domain. The functions of TRPM6 and TRPM7 are correlated with proteolytic cleavage of the kinase domain, which is then translocated to the nucleus to phosphorylate histones and regulate gene expression. Here we describe the structure of the TRPM7 transmembrane regions and compare its features to other ion channels. The transient receptor potential ion channel subfamily M, member 7 (TRPM7), is a ubiquitously expressed protein that is required for mouse embryonic development. TRPM7 contains both an ion channel and an α-kinase. The channel domain comprises a nonselective cation channel with notable permeability to Mg2+ and Zn2+. Here, we report the closed state structures of the mouse TRPM7 channel domain in three different ionic conditions to overall resolutions of 3.3, 3.7, and 4.1 Å. The structures reveal key residues for an ion binding site in the selectivity filter, with proposed partially hydrated Mg2+ ions occupying the center of the conduction pore. In high [Mg2+], a prominent external disulfide bond is found in the pore helix, which is essential for ion channel function. Our results provide a structural framework for understanding the TRPM1/3/6/7 subfamily and extend the knowledge base upon which to study the diversity and evolution of TRP channels.