STRUCTURE AND FUNCTION OF RECEPTORS AND TRANSPORTERS AT CHEMICAL SYNAPSES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 这一建议涉及两种不同和独特的膜蛋白：(1)真核细胞的P2X离子通道；(2)真核细胞的全长离子型谷氨酸受体(IGluR)。 第一个项目的重点是全长的P2X受体。P2X受体是一种ATP门控离子通道，仅存在于多细胞真核生物中，在神经系统中发挥关键作用(North，2002)。在氨基酸序列分析和其他实验室跨膜拓扑学研究的基础上，P2X受体定义了一个新的配体门控离子通道蛋白家族。我们已经在3.1？分辨率下解决了P2X受体的结构，并通过这样做定义了这一配体门控离子通道家族的分子结构。值得注意的是，P2X受体的结构也可能促进新型治疗剂的发展(Burnstock，2006；Franke等人，2006)。现在我们的目标是测量更高分辨率的数据--我们有了一种新的晶型--并收集与ATP结合的受体的衍射数据。 第二个项目涉及对谷氨酸门控离子通道晶体的研究，谷氨酸门控离子通道是人类神经系统中快速突触传递的关键。尽管人们对分离的谷氨酸结合域有很多了解，但对一个完整的受体的结构还没有原子知识。众所周知，iGluRs很难结晶，我们花了很多年才生产出第一个晶体。我们现在有了衍射率超过3.5？分辨率的晶体。

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.