Unit of Structural Dynamics of Macromolecules, Institut Pasteur and UMR 3528 du CNRS, 75015 Paris, France.
Department of Biochemistry and Biophysics and Science for Life Laboratory, Stockholm University, 17165 Solna, Sweden.
Cell Rep. 2018 Apr 24;23(4):993-1004. doi: 10.1016/j.celrep.2018.03.108.
Ion channel modulation by general anesthetics is a vital pharmacological process with implications for receptor biophysics and drug development. Functional studies have implicated conserved sites of both potentiation and inhibition in pentameric ligand-gated ion channels, but a detailed structural mechanism for these bimodal effects is lacking. The prokaryotic model protein GLIC recapitulates anesthetic modulation of human ion channels, and it is accessible to structure determination in both apparent open and closed states. Here, we report ten X-ray structures and electrophysiological characterization of GLIC variants in the presence and absence of general anesthetics, including the surgical agent propofol. We show that general anesthetics can allosterically favor closed channels by binding in the pore or favor open channels via various subsites in the transmembrane domain. Our results support an integrated, multi-site mechanism for allosteric modulation, and they provide atomic details of both potentiation and inhibition by one of the most common general anesthetics.
全麻药物对离子通道的调制是一个重要的药理学过程，涉及受体生物物理学和药物开发。功能研究表明，五聚体配体门控离子通道的增强和抑制作用都存在保守位点，但缺乏对这种双模态效应的详细结构机制。原核模型蛋白 GLIC 再现了人类离子通道的麻醉调制，并且可以在明显的开放和关闭状态下进行结构测定。在这里，我们报告了十个 X 射线结构和 GLIC 变体在存在和不存在全身麻醉剂（包括手术药物异丙酚）时的电生理学特征。我们表明，全身麻醉剂可以通过在孔中结合或通过跨膜域中的各种亚基来优先打开通道，从而变构地有利于关闭的通道。我们的结果支持变构调节的综合多部位机制，并提供了最常见的全身麻醉剂之一增强和抑制作用的原子细节。
