Sansom M S, Kerr I D
Laboratory of Molecular Biophysics, University of Oxford, UK.
Protein Eng. 1993 Jan;6(1):65-74. doi: 10.1093/protein/6.1.65.
The influenza A M2 protein forms cation-selective ion channels which are blocked by the anti-influenza drug amantadine. A molecular model of the M2 channel is presented in which a bundle of four parallel M2 transbilayer helices surrounds a central ion-permeable pore. Analysis of helix amphipathicity was used to aid determination of the orientation of the helices about their long axes. The helices are tilted such that the N-terminal mouth of the pore is wider than the C-terminal mouth. The channel is lined by residues V27, S31 and I42. Residues D24 and D44 are located at opposite mouths of the pore, which is narrowest in the vicinity of I42. Energy profiles for interaction of the channel with Na+, amantadine-H+ and cyclopentylamine-H+ are evaluated. The interaction profile for Na+ exhibits three minima, one at each mouth of the pore, and one in the region of residue S31. The amantadine-H+ profile exhibits a minimum close to S31 and a barrier near residue I42. This provides a molecular model for amantadine-H+ block of M2 channels. The profile for cyclopentylamine-H+ does not exhibit such a barrier. It is predicted that cyclopentylamine-H+ will not act as an M2 channel blocker.
甲型流感病毒M2蛋白形成阳离子选择性离子通道，抗流感药物金刚烷胺可阻断该通道。本文提出了M2通道的分子模型，其中四条平行的M2跨膜螺旋束围绕着一个中央离子渗透孔。通过分析螺旋两亲性来辅助确定螺旋围绕其长轴的方向。螺旋倾斜，使得孔的N端开口比C端开口宽。通道由V27、S31和I42残基构成内壁。D24和D44残基位于孔的相对开口处，孔在I42附近最窄。评估了通道与Na⁺、金刚烷胺-H⁺和环戊胺-H⁺相互作用的能量分布。Na⁺的相互作用分布呈现三个最小值，分别在孔的每个开口处以及残基S31区域。金刚烷胺-H⁺的分布在靠近S31处有一个最小值，在残基I42附近有一个屏障。这为金刚烷胺-H⁺对M2通道的阻断提供了一个分子模型。环戊胺-H⁺的分布没有显示出这样的屏障。预计环戊胺-H⁺不会作为M2通道阻滞剂起作用。
