X-ray Crystal Structure of the Influenza A M2 Proton Channel S31N Mutant in Two Conformational States: An Open and Shut Case
X-ray Crystal Structure of the Influenza A M2 Proton Channel S31N Mutant in Two Conformational States: An Open and Shut Case
复制标题
两种构象状态下甲型流感 M2 质子通道 S31N 突变体的 X 射线晶体结构：打开和关闭的情况
DOI：
10.1021/jacs.9b02196
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发表时间：
2019
影响因子：
15
通讯作者：
DeGrado, William F.
中科院分区：
文献类型：
--
作者：
Thomaston, Jessica L.;Wu, Yibing;Polizzi, Nicholas;Liu, Lijun;Wang, Jun;DeGrado, William F.
甲型流感M2质子通道的金刚烷胺耐药S31 N突变体在目前流行的病毒中已变得普遍。在这里，我们已经解决了X射线晶体结构的M2（22-46）S31 N，其中包含两个不同的构象状态内的不对称单元。该结构揭示了M2通道的两种构象状态下金刚烷抗性的机制。在内向开放构象中，突变体Asn 31侧链面向通道孔并在空间上阻断金刚烷结合位点。在内向闭合构象中，Asn 31与单体-单体界面上的羰基形成氢键，从而扭曲单体螺旋并收缩药物结合位点处的通道孔。我们还检查了M2（19-49）WT和S31 N使用溶液NMR光谱，并表明，这两种构象状态的分布取决于洗涤剂的选择和实验pH值。
The amantadine-resistant S31N mutant of the influenza A M2 proton channel has become prevalent in currently circulating viruses. Here, we have solved an X-ray crystal structure of M2(22–46) S31N that contains two distinct conformational states within its asymmetric unit. This structure reveals the mechanism of adamantane resistance in both conformational states of the M2 channel. In the Inwardopenconformation, the mutant Asn31 side chain faces the channel pore and sterically blocks the adamantane binding site. In the Inwardclosedconformation, Asn31 forms hydrogen bonds with carbonyls at the monomer–monomer interface, which twists the monomer helices and constricts the channel pore at the drug binding site. We also examine M2(19–49) WT and S31N using solution NMR spectroscopy and show that distribution of the two conformational states is dependent on both detergent choice and experimental pH.