Structures and gating mechanism of human TRPM2

Transient receptor potential (TRP) melastatin 2 (TRPM2) is a cation channel associated with numerous diseases. We determined the cryo‐EM structures of human TRPM2, alone, with ADPR, and with ADPR and Ca 2+ . The C‐terminal NUDT9H, in contrast to previously proposed felixible linking, 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. Ca 2+ 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 Ca 2+ and provide insights into the gating mechanism of other TRP channels. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .