Transient receptor potential melastatin 2 (TRPM2) is a Ca2+-permeable cation channel
required for immune cell activation, insulin secretion, and body heat control. TRPM2
is activated by cytosolic Ca2+, phosphatidyl-inositol-4,5-bisphosphate and ADP ribose.
Here, we present the 3 A resolution electron cryo-microscopic structure of TRPM2 from
Nematostella vectensis, 63% similar in sequence to human TRPM2, in the Ca2+-bound
closed state. Compared to other TRPM channels, TRPM2 exhibits unique structural features
that correlate with its function. The pore is larger and more negatively charged,
consistent with its high Ca2+ selectivity and larger conductance. The intracellular
Ca2+ binding sites are connected to the pore and cytosol, explaining the unusual dependence
of TRPM2 activity on intra- and extracellular Ca2+. In addition, the absence of a
post filter motif is likely the cause of the rapid inactivation of human TRPM2. Together,
our cryo-EM and electrophysiology studies provide a molecular understanding of the
unique gating mechanism of TRPM2.