This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This proposal involves two different and unique integral membrane proteins: (1) a eukaryotic P2X ion channel;and (2) a eukaryotic, full-length ionotropic glutamate receptor (iGluR). The first project is focused on a full-length P2X receptor. P2X receptors are ATP-gated ion channels that are present only in multicellular eukaryotes and that play key roles in the nervous system (North, 2002). On the basis of amino acid sequence analysis and on transmembrane topology studies carried out in other laboratories, P2X receptors define a novel family of ligand-gated ion channels proteins. We have solved the structure of a P2Xreceptor at 3.1 ? resolution and by doing so have defined the molecular architecture of this family of ligand-gated ion channels. Significantly, the structure of a P2X receptor may also facilitate the development of novel therapeutic agents (Burnstock, 2006;Franke et al., 2006). Now we aim to measure higher resolution data - we have a new crystal form - and to collect diffraction data on receptor bound with ATP. The second project involves studies of crystals of glutamate-gated ion channels, the linchpins of fast synaptic transmission in the human nervous system. Even though there is a great deal known about the isolated glutamate binding domain, there is no atomic knowledge of the structure of an intact receptor. iGluRs have proven notoriously difficult to crystallize and it has taken us many years to produce the first crystals. We now have crystals that diffract to beyond 3.5 ? resolution.
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