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首页> 外文期刊>Journal of Molecular Biology >Expect the Unexpected or Caveat for Drug Designers: Multiple Structure Determinations Using Aldose Reductase Crystals Treated under Varying Soaking and Co-crystallisation Conditions.
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Expect the Unexpected or Caveat for Drug Designers: Multiple Structure Determinations Using Aldose Reductase Crystals Treated under Varying Soaking and Co-crystallisation Conditions.

机译：对于药物设计人员来说，这是意料之外的事情或警告：使用在各种浸泡和共结晶条件下处理的醛糖还原酶晶体进行的多种结构测定。

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In structure-based drug design, accurate crystal structure determination of protein-ligand complexes is of utmost importance in order to elucidate the binding characteristics of a putative lead to a given target. It is the starting point for further design hypotheses to predict novel leads with improved properties. Often, crystal structure determination is regarded as ultimate proof for ligand binding providing detailed insight into the specific binding mode of the ligand to the protein. This widely accepted practise relies on the assumption that the crystal structure of a given protein-ligand complex is unique and independent of the protocol applied to produce the crystals. We present two examples indicating that this assumption is not generally given, even though the composition of the mother liquid for crystallisation was kept unchanged: Multiple crystal structure determinations of aldose reductase complexes obtained under varying crystallisation protocols concerning soaking and crystallisation exposure times were performed resulting in a total of 17 complete data sets and ten refined crystal structures, eight in complex with zopolrestat and two complexed with tolrestat. In the first example, a flip of a peptide bond is observed, obviously depending on the crystallisation protocol with respect to soaking and co-crystallisation conditions. This peptide flip is accompanied by a rupture of an H-bond formed to the bound ligand zopolrestat. The indicated enhanced local mobility of the complex is in agreement with the results of molecular dynamics simulations. As a second example, the aldose reductase-tolrestat complex is studied. Unexpectedly, two structures could be obtained: one with one, and a second with four inhibitor molecules bound to the protein. They are located in and near the binding pocket facilitated by crystal packing effects. Accommodation of the four ligand molecules is accompanied by pronounced shifts concerning two helices interacting with the additional ligands.
机译：在基于结构的药物设计中，蛋白质-配体复合物的准确晶体结构测定至关重要，以便阐明推定的引线与给定靶标的结合特征。这是进一步的设计假设的起点，以预测具有改进特性的新型引线。通常，晶体结构的确定被认为是配体结合的最终证据，可提供对配体与蛋白质的特定结合方式的详细了解。这种被广泛接受的做法是基于这样一个假设，即给定蛋白质-配体复合物的晶体结构是唯一的，并且与用于生产晶体的方案无关。我们提供了两个示例，表明即使结晶母液的组成保持不变，也无法普遍给出该假设：进行了关于浸泡和结晶暴露时间的不同结晶方案下获得的醛糖还原酶复合物的多晶体结构测定，结果总共17个完整的数据集和10个精炼的晶体结构，其中8个与zopolrestat配合使用，另外两个与tolrestat配合使用。在第一个例子中，观察到肽键的翻转，这显然取决于关于浸泡和共结晶条件的结晶方案。该肽翻转伴随着形成于结合的配体zopolrestat的H键的断裂。所指示的复合物的提高的局部迁移率与分子动力学模拟的结果一致。作为第二个例子，研究了醛糖还原酶-托来司他复合物。出乎意料的是，可以获得两种结构：一种具有与蛋白质结合的抑制剂分子，而另一种具有与蛋白质结合的四个抑制剂分子。它们位于装订袋中和附近，并通过晶体堆积效应得以促进。四个配体分子的适应伴随着涉及两个与额外配体相互作用的螺旋的明显变化。

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