Transient receptor potential (TRP) melastatin 2 (TRPM2) is a cation channel associated with numerous diseases. It has a C-terminal NUDT9 homology (NUDT9H) domain responsible for binding ADP-ribose (ADPR), and both ADPR and Ca2+ are required for TRPM2 activation. Here we report cryo-EM structures of human TRPM2, alone, with ADPR, and with ADPR and Ca2+.
NUDT9H forms both intra- and inter-subunit interactions with the N-terminal TRPM homology region (MHR1/2/3) in the apo state, but undergoes conformational changes upon ADPR binding, resulting in rotation of MHR1/2 and disruption of the inter-subunit interaction. Ca2+ binding further engages transmembrane helices and the conserved TRP helix to cause conformational changes at the MHR arm and the lower gating pore to potentiate channel opening.
These findings explain the molecular mechanism of concerted TRPM2 gating by ADPR and Ca2+ and provide insights into the gating mechanism of other TRP channels.