Structural investigation of rimantadine inhibition of the AM2-BM2 chimera channel of influenza viruses.
Structural investigation of rimantadine inhibition of the AM2-BM2 chimera channel of influenza viruses.
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DOI：
10.1016/j.str.2011.09.003
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发表时间：
2011-11-09
期刊：
影响因子：
5.7
通讯作者：
Chou, James J.
中科院分区：
文献类型：
--
作者：
Pielak, Rafal M.;Oxenoid, Kirill;Chou, James J.
甲型流感病毒的M2通道是金刚烷家族抗病毒药物的靶点。已经报道了两个不同的药物结合位点：一个在孔内，另一个是面向脂质的口袋。先前的一项研究表明，来自甲型和B型流感的M2变体的嵌合体仅含有孔结合位点，对金刚烷胺抑制敏感，这表明主要抑制位点在孔内。为了获得通道-药物相互作用的原子细节，我们确定了有和没有金刚乙胺的嵌合通道的结构。在通道内部和N-末端附近，来自四个亚基的Val 27和Ala 30的甲基在金刚烷周围形成疏水口袋，并且药物氨基似乎与Ala 30的主链氧极性接触。结构还揭示了可以解释耐药性的通道的药物结合和未结合状态之间的差异。
The M2 channel of influenza A is a target of the adamantane-family antiviral drugs. Two different drug-binding sites have been reported: one inside the pore and the other is a lipid-facing pocket. A previous study showed that a chimera of M2 variants from influenza A and B that contains only the pore-binding site is sensitive to amantadine inhibition, suggesting that the primary site of inhibition is inside the pore. To obtain atomic details of channel-drug interaction, we determined the structures of the chimeric channel with and without rimantadine. Inside the channel and near the N-terminal end, methyl groups of Val27 and Ala30 from four subunits form a hydrophobic pocket around the adamantane, and the drug amino group appears to be in polar contact with the backbone oxygen of Ala30. The structures also reveal differences between the drug bound and unbound states of the channel that can explain drug resistance.
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影响因子：
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影响因子：
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作者：
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10.1073/pnas.0811720106
发表时间：
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