Institut Pasteur, Groupe Récepteurs-Canaux, F-75015 Paris, France.
Structure. 2012 Jun 6;20(6):941-56. doi: 10.1016/j.str.2012.05.003.
Orthologs of the pentameric receptor channels that mediate fast synaptic transmission in the central and peripheral nervous systems have been found in several bacterial species and in a single archaea genus. Recent X-ray structures of bacterial and invertebrate pentameric receptors point to a striking conservation of the structural features within the whole family, even between distant prokaryotic and eukaryotic members. These structural data reveal general principles of molecular organization that allow allosteric membrane proteins to mediate chemoelectric transduction. Notably, several conformations have been solved, including open and closed channels with distinct global tertiary and quaternary structure. The data reveal features of the ion channel architecture and of diverse categories of binding sites, such as those that bind orthosteric ligands, including neurotransmitters, and those that bind allosteric modulators, such as general anesthetics, ivermectin, or lipids. In this review, we summarize the most recent data, discuss insights into the mechanism of action in these systems, and elaborate on newly opened avenues for drug design.
在几种细菌物种和一种古菌属中发现了介导中枢和外周神经系统快速突触传递的五聚体受体通道的同源物。细菌和无脊椎动物五聚体受体的最新 X 射线结构表明，整个家族内的结构特征惊人地保守，即使在远缘的原核生物和真核生物成员之间也是如此。这些结构数据揭示了允许变构膜蛋白介导化学-电转导的分子组织的一般原则。值得注意的是，已经解决了几种构象，包括具有独特全局三级和四级结构的开放和闭合通道。这些数据揭示了离子通道结构的特征和不同类别的结合位点，例如那些结合正位配体（包括神经递质）的结合位点，以及那些结合变构调节剂（如全身麻醉剂、伊维菌素或脂质）的结合位点。在这篇综述中，我们总结了最新的数据，讨论了这些系统中作用机制的见解，并详细阐述了药物设计的新途径。
