人們對全身麻醉的作用機制很不了解,，盡管一些證據(jù)表明它們的主要蛋白目標是“五聚配體門控離子通道” (pLGICs)?，F(xiàn)在,，與pLGIC家族一個細菌同系物結(jié)合在一起的異丙酚和地氟醚的X-射線晶體結(jié)構(gòu)已被確定,。這些結(jié)構(gòu)顯示了廣泛用在每個原體(protomer)跨膜域上半部分的這兩種麻醉藥的一個共同結(jié)合點,。這一全麻結(jié)合點為設計用來抑制或增強pLGICs的變構(gòu)性調(diào)控藥物的設計提供了一個模板,。（生物谷Bioon.com）
生物谷推薦原文出處：
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.
