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首页> 外文期刊>Journal of Molecular Biology >Bridging the gap between structural models of nicotinic receptor superfamily ion channels and their corresponding functional states.
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Bridging the gap between structural models of nicotinic receptor superfamily ion channels and their corresponding functional states.

机译：弥合烟碱样受体超家族离子通道的结构模型与其相应功能状态之间的差距。

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摘要

Aromatic-aromatic interactions are a prominent feature of the crystal structure of ELIC [Protein Data Bank (PDB) code 2VL0], a bacterial member of the nicotinic receptor superfamily of ion channels where five pore-facing phenylalanines come together to form a structure akin to a narrow iris that occludes the transmembrane pore. To identify the functional state of the channel that this structure represents, we engineered phenylalanines at various pore-facing positions of the muscle acetylcholine (ACh) receptor (one position at a time), including the position that aligns with the native phenylalanine 246 of ELIC, and assessed the consequences of such mutations using electrophysiological and toxin-binding assays. From our experiments, we conclude that the interaction among the side chains of pore-facing phenylalanines, rather than the accumulation of their independent effects, leads to the formation of a nonconductive conformation that is unresponsive to the application of ACh and is highly stable even in the absence of ligand. Moreover, electrophysiological recordings from a GLIC channel (another bacterial member of the superfamily) engineered to have a ring of phenylalanines at the corresponding pore-facing position suggest that this novel refractory state is distinct from the well-known desensitized state. It seems reasonable to propose then that it is in this peculiar nonconductive conformation that the ELIC channel was crystallized. It seems also reasonable to propose that, in the absence of rings of pore-facing aromatic side chains, such stable conformation may never be attained by the ACh receptor. Incidentally, we also noticed that the response of the proton-gated wild-type GLIC channel to a fast change in pH from pH 7.4 to pH 4.5 (on the extracellular side) is only transient, with the evoked current fading completely in a matter of seconds. This raises the possibility that the crystal structures of GLIC obtained at pH 4.0 (PDB code 3EHZ) and pH 4.6 (PDB code 3EAM) correspond to the to the (well-known) desensitized state.
机译：芳香-芳香相互作用是ELIC [蛋白质数据库（PDB）代码2VL0]的晶体结构的显着特征，ELIC是离子通道烟碱受体超家族的细菌成员，其中五个面对孔的苯丙氨酸共同形成一个类似于狭窄的虹膜闭塞了跨膜孔。为了确定该结构所代表的通道​​的功能状态，我们在肌肉乙酰胆碱（ACh）受体的各个面向孔的位置（一次一个位置），包括与ELIC的天然苯丙氨酸246对齐的位置，对苯丙氨酸进行了工程改造，并使用电生理和毒素结合试验评估了此类突变的后果。从我们的实验中，我们得出结论，面向孔的苯丙氨酸侧链之间的相互作用，而不是其独立作用的积累，导致形成了对ACh的应用无响应并且即使在不存在配体。此外，来自GLIC通道（超家族的另一个细菌成员）的电生理记录经工程改造，在相应的面向孔的位置具有苯丙氨酸环，这表明这种新的难治性状态与众所周知的脱敏状态不同。因此，似乎合理的建议是，以这种特殊的非导电构造使ELIC通道结晶。提出在没有面对孔的芳香族侧链的环的情况下，ACh受体可能永远无法获得这种稳定的构象，这似乎也是合理的。顺便说一句，我们还注意到质子门控野生型GLIC通道对pH从pH 7.4迅速变化到pH 4.5（在细胞外）的响应只是短暂的，诱发的电流在大约20分钟内完全消失。秒。这增加了在pH 4.0（PDB代码3EHZ）和pH 4.6（PDB代码3EAM）下获得的GLIC晶体结构对应于（众所周知的）脱敏状态的可能性。

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