打开疏水门：以烟碱乙酰胆碱受体为例
Opening a hydrophobic gate: the nicotinic acetylcholine receptor as an example
摘要：
疏水门必须扩张到什么程度才算通道打开？我们解决这个问题使用烟碱乙酰胆碱受体（nAChR）为例。nAChR是一种整合的膜蛋白，其形成由神经递质结合至其胞外结构域的阳离子选择性通道。已经提出了一个疏水门控模型的nAChR，其中孔是不完全封闭在封闭状态的通道，与一个狭窄的疏水性的中央门区域，它提出了一个充满活力的障碍离子渗透。nAChR孔由五个M2 α-螺旋的平行束排列，门由三个疏水侧链环（M2的9 '，13'和17'）形成。已经提出了许多模型来描述nAChR的封闭到开放过渡的基础上的构象变化的性质。这些模型涉及不同程度的M2螺旋位移、旋转和/或扭结。在这项研究中，我们使用一个简单的孔扩张方法（以前用于模型开放的钾通道），以产生一系列逐步扩大模型的nAChR跨膜结构域。连续体静电计算用于评估作为孔膨胀的函数的疏水门的势垒高度的变化。结果表明，Δ r ~ 1.5埃的半径的增加足以在功能上打开孔，而不需要例如M2螺旋的旋转。这是评估的背景下，目前的突变和结构数据的nAChR及其同系物。
英文摘要：
To what extent must a hydrophobic gate expand for the channel to count as open? We address this question using the nicotinic acetylcholine receptor (nAChR) as the exemplar. The nAChR is an integral membrane protein which forms a cation selective channel gated by neurotransmitter binding to its extracellular domain. A hydrophobic gating model has been proposed for the nAChR, whereby the pore is incompletely occluded in the closed state channel, with a narrow hydrophobic central gate region which presents an energetic barrier to ion permeation. The nAChR pore is lined by a parallel bundle of five M2 alpha-helices, with the gate formed by three rings of hydrophobic sidechains (9', 13', and 17' of M2). A number of models have been proposed to describe the nature of the conformational change underlying the closed to open transition of the nAChR. These models involve different degrees of M2 helix displacement, rotation, and/or kinking. In this study, we use a simple pore expansion method (previously used to model opening of potassium channels) to generate a series of progressively wider models of the nAChR transmembrane domain. Continuum electrostatics calculations are used to assess the change in the barrier height of the hydrophobic gate as a function of pore expansion. The results suggest that an increase in radius of Delta r ~ 1.5 angstrom is sufficient to functionally open the pore without, for example, a requirement for rotation of the M2 helices. This is evaluated in the context of current mutational and structural data on the nAChR and its homologues.
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