Rigid body essential X-ray crystallography: Distinguishing the bend and twist of glutamate receptor ligand binding domains
Rigid body essential X-ray crystallography: Distinguishing the bend and twist of glutamate receptor ligand binding domains
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DOI：
10.1002/prot.21941
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发表时间：
2008-07-01
影响因子：
2.9
通讯作者：
Biggin, Philip C.
中科院分区：
文献类型：
--
作者：
Bjerrum, Esben J.;Biggin, Philip C.
来自离子型谷氨酸受体亚型2（GluR 2）的配体结合结构域（LBD）已被证明采用一系列配体依赖性构象状态。这些状态已经根据在子域（波瓣）1的叠加之后拟合子域（波瓣）2所需的旋转来描述。LBD具有完全激动剂的闭合裂缝构象，但部分激动剂诱导一系列闭合，这反过来控制全长受体中离散亚电导状态的开放概率。虽然这种描述是有用的，但它可能无法解释受体经历的所有生理学上重要的运动。我们已经使用了一种方法，结合基本动力学和刚体动力学的方法来分析124个单体域从55个晶体结构的GluR 2 LBD。我们能够表明，部分激动剂也会诱导大量的扭曲，这将不会使用一个旋转描述符之间的载脂蛋白和完全激动剂结合状态的预期。此外，晶体结构之一（来自1 P1 U的链B，GluR 2 L 650 T-AMPA复合物）被认为代表受体的激动剂结合的无活性形式，位于这种扭转运动的极端。我们认为，部分激动剂不仅阻止完全关闭，但也移动受体更接近这种非活性状态。我们还演示了该方法如何可以用来比较分子动力学模拟的结果与晶体学数据和在何种程度上探索的构象空间的重叠。
The ligand-binding domain (LBD) from the ionotropic glutamate receptor subtype 2 (GluR2) has been shown to adopt a range of ligand-dependent conformational states. These states have been described in terms of the rotation required to fit subdomain (lobe) 2 following superposition of subdomain (lobe) 1. The LBD has a closed-cleft conformation for full agonists, but partial agonists induce a range of closure, which in turn controls the open probability of discrete subconductance states in the full-length receptor. Although this description is useful, it may not account for all physiologically important motions that the receptor undergoes. We have used an approach that combines the methods of essential dynamics and rigid-body dynamics to analyze 124 monomer domains from 55 crystal structures of the GluR2 LBD. We are able to show that partial agonists also induce a significant amount of twist that would not be anticipated using one rotational descriptor between apo and full-agonist-bound states. Furthermore, one of the crystal structures (chain B from 1P1U, the GluR2 L650T-AMPA complex), which has been suggested to represent an agonist-bound inactive form of the receptor, lies at the extreme of this twist motion. We suggest that partial agonists not only prevent full closure but also move the receptor closer to this inactive state. We demonstrate additionally how the method can be used to compare the results of molecular dynamics simulations with the crystallographic data and the extent to which the conformational space explored by both overlaps.