Structural coupling between FKBP12 and buried water.
Structural coupling between FKBP12 and buried water.
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DOI：
10.1002/prot.22176
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发表时间：
2009-02-15
影响因子：
2.9
通讯作者：
Saven, Jeffery G.
中科院分区：
文献类型：
--
作者：
Szep, Szilvia;Park, Sheldon;Boder, Eric T.;Van Duyne, Gregory D.;Saven, Jeffery G.
球状蛋白质通常含有结构良好的内部水分子。以前，我们报告的结果，从分子动力学研究表明，一个埋藏的水（瓦特3）可能发挥作用，在调节FK 506结合蛋白-12（FKBP 12）的结构。特别是，模拟表明，通过将E60突变为A或Q来破坏与Wat 3的氢键将导致涉及远处W59侧链的结构扰动，该侧链响应于突变而旋转到新的构象。这有效地重塑了配体结合口袋，因为新构象中的侧链可能与结合的FK 506冲突。为了测试蛋白质结构是否有效地被远处埋藏的水的结合所调节，我们通过X射线晶体学确定了野生型FKBP 12及其两个突变体（E60 A，E60 Q）的高分辨率（0.92 - 1.29 μ m）结构。突变体FKBP 12的结构表明，配体结合口袋确实如通过在位置60处的取代所预测的那样被重塑，即使水分子不直接与结合口袋的任何氨基酸相互作用。因此，这些结构支持这样的观点，即埋藏的水分子构成了蛋白质结构的一个完整的非共价组分。此外，这项研究提供了一个例子，其中分子动力学模拟的预测与原子精度的实验验证，从而表明，蛋白质-水相互作用的结构特征可以在分子水平上可靠地建模。
Globular proteins often contain structurally well-resolved internal water molecules. Previously, we reported results from a molecular dynamics study that suggested that a buried water (Wat3) may play a role in modulating the structure of the FK506 binding protein-12 (FKBP12). In particular, simulations suggested that disrupting a hydrogen bond to Wat3 by mutating E60 to either A or Q would cause a structural perturbation involving the distant W59 side chain, which rotates to a new conformation in response to the mutation. This effectively remodels the ligand binding pocket, as the side chain in the new conformation is likely to clash with bound FK506. To test if the protein structure is in effect modulated by the binding of a buried water in the distance, we determined high resolution (0.92 – 1.29 Å) structures of wild type FKBP12 and its two mutants (E60A, E60Q) by x-ray crystallography. The structures of mutant FKBP12 show that the ligand-binding pocket is indeed remodeled as predicted by the substitution at position 60, even though the water molecule does not directly interact with any of the amino acids of the binding pocket. Thus, these structures support the view that buried water molecules constitute an integral, noncovalent component of the protein structure. Additionally, this study provides an example in which predictions from molecular dynamics simulations are experimentally validated with atomic precision, thus showing that the structural features of protein-water interactions can be reliably modeled at a molecular level.
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DOI：
10.1093/protein/7.5.613
发表时间：
1994-05-01
期刊：
PROTEIN ENGINEERING
影响因子：
--
作者：
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影响因子：
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发表时间：
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影响因子：
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通讯作者：
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影响因子：
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作者：
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影响因子：
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作者：
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