Structure of a potentially open state of a proton-activated pentameric ligand-gated ion channel
Structure of a potentially open state of a proton-activated pentameric ligand-gated ion channel
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DOI：
10.1038/nature07461
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发表时间：
2009-01-01
期刊：
影响因子：
64.8
通讯作者：
Dutzler, Raimund
中科院分区：
文献类型：
--
作者：
Hilf, Ricarda J. C.;Dutzler, Raimund
来自欧文氏菌的五聚体配体门控离子通道（ELIC）的X射线结构最近以高分辨率提供了对该离子通道家族的结构洞察（1）。该结构显示了具有桶形结构的同源五聚体蛋白质，该桶形结构限定了位于五重对称轴上的离子传导孔。在这种结构中，由五个亚基的细胞外配体结合结构域包围的宽水性前庭变窄为跨越脂质双层的不连续孔。孔被朝向细胞外侧的大体积疏水残基收缩，这可能充当阻止离子扩散的屏障。因此，ELIC中的这种中断的孔结构描绘了五聚体配体门控离子通道的非导电构象，即在不存在结合配体的情况下的化学稳定状态。由于配体结合促进这些离子通道中的孔开放，并且尚未鉴定ELIC的特异性配体，因此我们将注意力转向来自蓝细菌Gloebacter violaceus（GLIC）的同源蛋白。GLIC显示形成质子门控通道，其通过细胞外侧的pH降低而被激活，并且在激活后不脱敏（2）。两种原核蛋白质ELIC和GLIC形成离子通道，其对阳离子的选择性优于对阴离子的选择性，对一价阳离子的区分较差（1，2），其特征类似于包括乙酰胆碱和5-羟色胺受体的家族的阳离子选择性分支的传导性质（3，4）.本文给出了GLIC在3.1埃分辨率下的X射线结构.该结构揭示了不同于ELIC的通道的构象，并且可能类似于开放状态。结合起来，这两种结构表明了五聚体配体门控离子通道的一种新的门控机制，其中通道开放通过成孔螺旋的倾斜变化进行。
The X- ray structure of a pentameric ligand- gated ion channel from Erwinia chrysanthemi ( ELIC) has recently provided structural insight into this family of ion channels at high resolution(1). The structure shows a homo- pentameric protein with a barrel- stave architecture that defines an ion- conduction pore located on the fivefold axis of symmetry. In this structure, the wide aqueous vestibule that is encircled by the extracellular ligand- binding domains of the five subunits narrows to a discontinuous pore that spans the lipid bilayer. The pore is constricted by bulky hydrophobic residues towards the extracellular side, which probably serve as barriers that prevent the diffusion of ions. This interrupted pore architecture in ELIC thus depicts a non- conducting conformation of a pentameric ligand- gated ion channel, the thermodynamically stable state in the absence of bound ligand. As ligand binding promotes pore opening in these ion channels and the specific ligand for ELIC has not yet been identified, we have turned our attention towards a homologous protein from the cyanobacterium Gloebacter violaceus ( GLIC). GLIC was shown to form proton- gated channels that are activated by a pH decrease on the extracellular side and that do not desensitize after activation(2). Both prokaryotic proteins, ELIC and GLIC form ion channels that are selective for cations over anions with poor discrimination among monovalent cations(1,2), characteristics that resemble the conduction properties of the cation- selective branch of the family that includes acetylcholine and serotonin receptors(3,4). Here we present the X- ray structure of GLIC at 3.1 angstrom resolution. The structure reveals a conformation of the channel that is distinct from ELIC and that probably resembles the open state. In combination, both structures suggest a novel gating mechanism for pentameric ligand- gated ion channels where channel opening proceeds by a change in the tilt of the pore- forming helices.