Autocrine and paracrine signaling via extracellular nucleotides are one of the most ubiquitous signaling mechanisms in the mammalian organism. Cells release nucleotides both by exocytosis and through large pores in the plasma membrane. Pannexins are non-selective channels that open a 10nm pore, allowing for ATP release in many signaling events. These channels have been shown to play essential roles in vasodilation/vasoconstriction, activation of the inflammasome, the taste sensation, glia-neuron communication, and apoptosis. This wide variety of physiological roles suggests multiple channel mechanisms or protein activators, the details of which are difficult to understand in the absence of a high-resolution structure. In this work, purification of pannexin is established and protein crystals obtained. Weakly diffracting crystals are improved through a combination of biochemistry and protein engineering. These important steps on the path towards structure determination have revealed some insights into the function of this unique channel protein.