Correlating AMPA receptor activation and cleft closure across subunits: crystal structures of the GluR4 ligand-binding domain in complex with full and partial agonists.
Correlating AMPA receptor activation and cleft closure across subunits: crystal structures of the GluR4 ligand-binding domain in complex with full and partial agonists.
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关联 AMPA 受体激活和跨亚基裂口闭合：与完全和部分激动剂复合的 GluR4 配体结合结构域的晶体结构。
DOI：
10.1021/bi8013196
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发表时间：
2008-12-30
期刊：
影响因子：
2.9
通讯作者：
Madden, Dean R.
中科院分区：
文献类型：
--
作者：
Gill, Avinash;Birdsey-Benson, Amanda;Jones, Brian L.;Henderson, Leslie P.;Madden, Dean R.
AMPA受体是谷氨酸门控离子通道，是中枢神经系统中突触信号的重要介质。它们形成四聚体，组装成亚基GluR 1 -4的组合，每个亚基都含有配体结合结构域（LBD）。GluR 2 LBD的晶体结构揭示了一个激动剂结合裂缝，它位于两个裂片之间，就像一个捕蝇草。一般来说，激动剂的疗效与裂隙闭合的程度相关。然而，最近的观察表明，裂隙闭合不是谷氨酸受体相对功效的唯一决定因素。此外，这些研究集中在GluR 2亚基上，这是体内生理学上重要的RNA编辑修饰的特异性靶点。因此，我们希望测试裂缝闭合的一般性：其他AMPA-R亚基的功效相关性。在这里，我们提出了晶体结构的GluR 4翻转LBD在复杂的全部和部分激动剂。至于GluR 2，两种激动剂都稳定了闭合裂缝构象，并且部分激动剂诱导的裂缝闭合比完全激动剂小。然而，LBD：红藻氨酸相互作用的详细分析揭示了在确定激动剂相关的构象变化的幅度的配体结合口袋中的细微骨架构象变化的重要性。此外，GluR 4亚基表现出不同的受体激活和LBD裂缝关闭之间的相关性比GluR 2。
AMPA receptors are glutamate-gated ion channels that are essential mediators of synaptic signals in the central nervous system. They form tetramers that are assembled as combinations of the subunits GluR1-4, each of which contains a ligand-binding domain (LBD). Crystal structures of the GluR2 LBD have revealed an agonist-binding cleft, which is located between two lobes and which acts like a Venus flytrap. In general, agonist efficacy is correlated with the extent of cleft closure. However, recent observations show that cleft closure is not the sole determinant of relative efficacy for glutamate receptors. In addition, these studies have focused on the GluR2 subunit, which is the specific target of a physiologically important RNA-editing modification in vivo. We therefore wished to test the generality of the cleft closure:efficacy correlation for other AMPA-R subunits. Here, we present crystal structures of the GluR4flip LBD in complex with both full and partial agonists. As for GluR2, both agonists stabilize a closed-cleft conformation, and the partial agonist induces a smaller cleft closure than the full agonist. However, a detailed analysis of LBD:kainate interactions reveals the importance of subtle backbone conformational changes in the ligand-binding pocket in determining the magnitude of agonist-associated conformational changes. Furthermore, the GluR4 subunit exhibits a different correlation between receptor activation and LBD cleft closure than does GluR2.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
DOI：
10.1073/pnas.1037393100
发表时间：
2003-05-13
影响因子：
11.1
作者：
Armstrong, N;Mayer, M;Gouaux, E
通讯作者：
Gouaux, E
影响因子：
16.2
作者：
Inanobe, A;Furukawa, H;Gouaux, E
通讯作者：
Gouaux, E
影响因子：
7.3
作者：
Jensen, Anders A.;Christesen, Thomas;Clausen, Rasmus P.
通讯作者：
Clausen, Rasmus P.
影响因子：
56.9
作者：
KEINANEN, K;WISDEN, W;SEEBURG, PH
通讯作者：
SEEBURG, PH