人们对全身麻醉的作用机制很不了解，尽管一些证据表明它们的主要蛋白目标是“五聚配体门控离子通道” (pLGICs)。现在，与pLGIC家族一个细菌同系物结合在一起的异丙酚和地氟醚的X-射线晶体结构已被确定。这些结构显示了广泛用在每个原体(protomer)跨膜域上半部分的这两种麻醉药的一个共同结合点。这一全麻结合点为设计用来抑制或增强pLGICs的变构性调控药物的设计提供了一个模板。（生物谷Bioon.com）
生物谷推荐原文出处：
Nature doi:10.1038/nature09647
X-ray structures of general anaesthetics bound to a pentameric ligand-gated ion channel
Hugues Nury,Catherine Van Renterghem,Yun Weng,Alphonso Tran,Marc Baaden,Virginie Dufresne,Jean-Pierre Changeux,James M. Sonner,Marc Delarue& Pierre-Jean Corringer
General anaesthetics have enjoyed long and widespread use but their molecular mechanism of action remains poorly understood. There is good evidence that their principal targets are pentameric ligand-gated ion channels1, 2 (pLGICs) such as inhibitory GABAA (γ-aminobutyric acid) receptors and excitatory nicotinic acetylcholine receptors, which are respectively potentiated and inhibited by general anaesthetics. The bacterial homologue from Gloeobacter violaceus3 (GLIC), whose X-ray structure was recently solved4, 5, is also sensitive to clinical concentrations of general anaesthetics6. Here we describe the crystal structures of the complexes propofol/GLIC and desflurane/GLIC. These reveal a common general-anaesthetic binding site, which pre-exists in the apo-structure in the upper part of the transmembrane domain of each protomer. Both molecules establish van der Waals interactions with the protein; propofol binds at the entrance of the cavity whereas the smaller, more flexible, desflurane binds deeper inside. Mutations of some amino acids lining the binding site profoundly alter the ionic response of GLIC to protons, and affect its general-anaesthetic pharmacology. Molecular dynamics simulations, performed on the wild type (WT) and two GLIC mutants, highlight differences in mobility of propofol in its binding site and help to explain these effects. These data provide a novel structural framework for the design of general anaesthetics and of allosteric modulators of brain pLGICs.
