Architecture of the human TRPM2 channel Adenosine diphosphate–ribose (ADPR) mediates calcium (Ca 2+ ) release by activating the transient receptor potential melastatin 2 (TRPM2) channel. Three structures now elucidate the conformational regulation mechanism of TRPM2 gating. Wang et al. describe cryo–electron microscopy structures of human TRPM2 in the apo, ADPR-bound, and ADPR- and Ca 2+ -bound states. In the apo state, both intra- and intersubunit interactions appeared to lock TRPM2 into a closed and autoinhibited state. ADPR binding disrupted some interactions and dramatically altered the TRPM2 conformation. Binding of Ca 2+ further primed the opening of the channel. Science , this issue p. eaav4809