Structural basis for the function and inhibition of an influenza virus proton channel
Structural basis for the function and inhibition of an influenza virus proton channel
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DOI：
10.1038/nature06528
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发表时间：
2008-01-31
期刊：
影响因子：
64.8
通讯作者：
DeGrado, William F.
中科院分区：
文献类型：
--
作者：
Stouffer, Amanda L.;Acharya, Rudresh;DeGrado, William F.
甲型流感病毒的M2蛋白是一种pH激活的质子通道，它介导内体中所包裹病毒颗粒内部的酸化。M2是抗流感药物金刚烷胺和金刚乙胺的作用靶点；近期，人类、禽类和猪对这些药物的耐药性已超过90%（参考文献1）。在此我们描述了在有和没有通道阻断药物金刚烷胺存在的情况下，同型四聚体蛋白跨膜区域的晶体结构。在一组参与质子门控的保守组氨酸和色氨酸残基附近发生pH依赖性结构变化（2）。药物结合位点由在耐金刚烷胺病毒中发生突变的残基排列而成（3,4）。金刚烷胺的结合从物理上阻塞了孔隙，并且可能还会干扰关键组氨酸残基的pK(a)。该结构为解决对M2通道阻滞剂的耐药性问题提供了一个起点。
The M2 protein from influenza A virus is a pH- activated proton channel that mediates acidification of the interior of viral particles entrapped in endosomes. M2 is the target of the anti- influenza drugs amantadine and rimantadine; recently, resistance to these drugs in humans, birds and pigs has reached more than 90% ( ref. 1). Here we describe the crystal structure of the transmembrane- spanning region of the homotetrameric protein in the presence and absence of the channel- blocking drug amantadine. pH- dependent structural changes occur near a set of conserved His and Trp residues that are involved in proton gating(2). The drug- binding site is lined by residues that are mutated in amantadine- resistant viruses(3,4). Binding of amantadine physically occludes the pore, and might also perturb the pK(a) of the critical His residue. The structure provides a starting point for solving the problem of resistance to M2- channel blockers.