The crystal structure of TRPM2 MHR1/2 domain reveals a conserved Zn(2+)‐binding domain essential for structural integrity and channel activity

Transient receptor potential melastatin 2 (TRPM2) is a Ca(2+)‐permeable, nonselective cation channel involved in diverse physiological processes such as immune response, apoptosis, and body temperature sensing. TRPM2 is activated by ADP‐ribose (ADPR) and 2′‐deoxy‐ADPR in a Ca(2+)‐dependent manner. While two distinct binding sites exist for ADPR that exert different functions dependent on the species, the involvement of either binding site regarding the superagonistic effect of 2′‐deoxy‐ADPR is not clear yet. Here, we report the crystal structure of the MHR1/2 domain of TRPM2 from zebrafish (Danio rerio), and show that both ligands bind to this domain and activate the channel. We identified a so far unrecognized Zn(2+)‐binding domain that was not resolved in previous cryo‐EM structures and that is conserved in most TRPM channels. In combination with patch clamp experiments we comprehensively characterize the effect of the Zn(2+)‐binding domain on TRPM2 activation. Our results provide insight into a conserved motif essential for structural integrity and channel activity.