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Dynamic closed states of a ligand-gated ion channel captured by cryo-EM and simulations.
Life Science Alliance ( IF 3.3 ) Pub Date : 2021-07-01 , DOI: 10.26508/lsa.202101011
Urška Rovšnik 1 , Yuxuan Zhuang 1 , Björn O Forsberg 1, 2 , Marta Carroni 1 , Linnea Yvonnesdotter 1 , Rebecca J Howard 1 , Erik Lindahl 3, 4
Affiliation  

Ligand-gated ion channels are critical mediators of electrochemical signal transduction across evolution. Biophysical and pharmacological characterization of these receptor proteins relies on high-quality structures in multiple, subtly distinct functional states. However, structural data in this family remain limited, particularly for resting and intermediate states on the activation pathway. Here, we report cryo-electron microscopy (cryo-EM) structures of the proton-activated Gloeobacter violaceus ligand-gated ion channel (GLIC) under three pH conditions. Decreased pH was associated with improved resolution and side chain rearrangements at the subunit/domain interface, particularly involving functionally important residues in the β1-β2 and M2-M3 loops. Molecular dynamics simulations substantiated flexibility in the closed-channel extracellular domains relative to the transmembrane ones and supported electrostatic remodeling around E35 and E243 in proton-induced gating. Exploration of secondary cryo-EM classes further indicated a low-pH population with an expanded pore. These results allow us to define distinct protonation and activation steps in pH-stimulated conformational cycling in GLIC, including interfacial rearrangements largely conserved in the pentameric channel family.

中文翻译:


通过冷冻电镜和模拟捕获配体门控离子通道的动态闭合状态。



配体门控离子通道是进化过程中电化学信号转导的关键介质。这些受体蛋白的生物物理和药理学特征依赖于多种、微妙不同的功能状态下的高质量结构。然而,该家族的结构数据仍然有限,特别是对于激活途径的静息状态和中间状态。在这里,我们报告了质子激活紫罗兰胶杆菌配体门控离子通道 (GLIC) 在三种 pH 条件下的冷冻电子显微镜 (cryo-EM) 结构。 pH 值降低与亚基/结构域界面处的分辨率提高和侧链重排相关,特别是涉及 β1-β2 和 M2-M3 环中功能重要的残基。分子动力学模拟证实了闭通道细胞外域相对于跨膜域的灵活性,并支持质子诱导门控中 E35 和 E243 周围的静电重塑。对二级冷冻电镜类别的探索进一步表明具有扩大孔的低 pH 群体。这些结果使我们能够定义 GLIC 中 pH 刺激的构象循环中不同的质子化和激活步骤,包括在五聚体通道家族中很大程度上保守的界面重排。
更新日期:2021-07-05
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