The publication of the first crystal structures of the zebrafish P2X4 receptor in 2009 was a pivotal
moment; for the first time, researchers were able to interpret their experimental data in a structural context.
Several research groups immediately set about using the data to make molecular models of the betterunderstood
mammalian P2X receptors, in order to design and interpret the results of new, more focused structure-
function experiments. In 2012, the publication of the crystal structure of zebrafish P2X4 in the ATPbound
state gave further insights into the mechanism of ligand binding and its coupling to ion channel activation,
initiating a new cycle of modelling, experimentation and interpretation. The purpose of this review is to describe our
current understanding of the 3D-structure of P2X receptors, by highlighting the strengths and limitations of the zebrafish
P2X4 crystal structures, discussing how the molecular models derived from them have been made, and what they have
been used for, and explaining why crystal structures of mammalian P2X receptors are still needed to uncover the molecular
mechanisms of differential agonist/antagonist potency, allosteric modulation, pore dilatation and desensitisation.