Pannexins (Panx1-3) constitute a unique family of large-pore forming channels that control the release of signaling molecules including ATP. Dysregulated ATP release via Panx1 has been implicated in inflammation-related pathology affecting the immune, cardiovascular, and nervous systems, such as asthma, aortic aneurysm, atherosclerosis, and ischemic neuron death. While significant progress has been made in discerning the opening of pannexin channels, the mechanism governing their closure remains elusive. The specific objective of my research is to understand how pannexin channels prevent ATP and other ions from moving in and out of the pore at the resting and closed state. I will achieve this goal by determining cryogenic-electron microscopy (cryo-EM) structures of Panx1 truncated to the minimum components. By comparing the two cryo-EM maps in its open and closed states, I expect to discover an important conformational change associated with the channel gating. Successful completion of my study should not only advance our comprehension of the processes governing the release of ATP into the extracellular space, but also unveil a novel gating mechanism for large-pore forming channels.