Elucidation of Ligand-Dependent Modulation of Disorder-Order Transitions in the Oncoprotein MDM2.
Elucidation of Ligand-Dependent Modulation of Disorder-Order Transitions in the Oncoprotein MDM2.
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DOI：
10.1371/journal.pcbi.1004282
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发表时间：
2015-06
影响因子：
4.3
通讯作者：
Michel J
中科院分区：
文献类型：
--
作者：
Bueren-Calabuig JA;Michel J
许多生物分子相互作用涉及非结构化蛋白质区域，但如何在合理的药物设计背景下利用这种相互作用来增强先导分子的亲和力仍然不确定。这里寻求澄清不同配体与相同无序蛋白质区域的相互作用产生性质不同的结果的情况。具体来说，通过加速分子动力学、伞式采样和变分自由能谱方法的新颖组合，计算了在不同配体存在下癌蛋白 MDM2 N 端结构域无序盖区域的构象集合。由此产生的 MDM2 构象整体（游离的和与 p53 TAD (17-29) 肽结合的）识别出与之前的 NMR 测量兼容的盖子状态。值得注意的是，MDM2 盖区域在不同小分子配体存在的情况下呈现出不同的构象状态。小分子结合体的详细分析表明，大约。哌啶酮家族抑制剂对 MDM2 构建体（包括全盖）的亲和力提高了 25 倍，这与配体疏水基团和 apo MDM2 中已部分有序的 C 端盖区域之间的相互作用相关。相比之下，Nutlin 或苯二氮卓类抑制剂以相似的亲和力与全盖和盖截短的 MDM2 构建体结合，另外通过其增溶基团与 apo MDM2 中更无序的 N 端盖残基相互作用。我们知道生命取决于蛋白质之间的相互作用。有大量证据表明蛋白质之间的许多相互作用涉及非常灵活的蛋白质区域。这些无序区域在与另一种蛋白质形成相互作用时可能会经历无序/有序转变。许多成功的药物化学方法都是基于模拟生物分子与人造小分子的相互作用。然而，目前人们对类药物小分子如何调节蛋白质紊乱知之甚少，很大程度上是因为很难用实验方法详细测量这种类型的相互作用。在这里，我们使用计算机模拟来详细解析不同小分子调节蛋白质 MDM2 无序区域的灵活性的过程。这种蛋白质在许多癌症中过度表达，并且在过去十年中已开发出识别 MDM2 的小分子，作为可能的新型抗癌药物。我们表明，灵活的 MDM2“盖子”区域在存在不同小分子的情况下采用不同的构象状态。我们的结果表明了为什么某些类别的小分子与盖子区域形成有利的相互作用，而其他类别则不然。这些发现可能对开发新的、更有效的 MDM2 抑制剂至关重要，更广泛地说，有助于药物设计者用小分子靶向无序蛋白质区域。
Numerous biomolecular interactions involve unstructured protein regions, but how to exploit such interactions to enhance the affinity of a lead molecule in the context of rational drug design remains uncertain. Here clarification was sought for cases where interactions of different ligands with the same disordered protein region yield qualitatively different results. Specifically, conformational ensembles for the disordered lid region of the N-terminal domain of the oncoprotein MDM2 in the presence of different ligands were computed by means of a novel combination of accelerated molecular dynamics, umbrella sampling, and variational free energy profile methodologies. The resulting conformational ensembles for MDM2, free and bound to p53 TAD (17-29) peptide identify lid states compatible with previous NMR measurements. Remarkably, the MDM2 lid region is shown to adopt distinct conformational states in the presence of different small-molecule ligands. Detailed analyses of small-molecule bound ensembles reveal that the ca. 25-fold affinity improvement of the piperidinone family of inhibitors for MDM2 constructs that include the full lid correlates with interactions between ligand hydrophobic groups and the C-terminal lid region that is already partially ordered in apo MDM2. By contrast, Nutlin or benzodiazepinedione inhibitors, that bind with similar affinity to full lid and lid-truncated MDM2 constructs, interact additionally through their solubilizing groups with N-terminal lid residues that are more disordered in apo MDM2. Life as we know it depends on interactions between proteins. There is substantial evidence that many interactions between proteins involve very flexible protein regions. These disordered regions may undergo disorder/order transitions upon forming an interaction with another protein. Many successful approaches to medicinal chemistry are based on mimicking the interactions of biological molecules with man-made small molecules. However how drug-like small-molecules may modulate protein disorder is currently poorly understood, largely because it is difficult to measure in details this type of interaction with experimental methods. Here we have used computer simulations to resolve with great details the process by which different small-molecules modulate the flexibility of a disordered region of the protein MDM2. This protein is overexpressed in many cancers and small-molecules that recognize MDM2 have been developed over the last decade as possible novel anti-cancer agents. We show that the flexible MDM2 “lid” region adopts different conformational states in the presence of different small-molecules. Our results suggest why some classes of small-molecules form favorable interactions with the lid region, whereas others do not. These findings may prove crucial to develop new and more effective MDM2 inhibitors, and more generally to help drug designers target disordered proteins regions with small-molecules.
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影响因子：
3.9
作者：
Cuchillo, Remi;Michel, Julien
通讯作者：
Michel, Julien
影响因子：
3
作者：
Dastidar SG;Lane DP;Verma CS
通讯作者：
Verma CS
影响因子：
2.9
作者：
Best, Robert B.;Mittal, Jeetain
通讯作者：
Mittal, Jeetain
影响因子：
4.3
作者：
Dastidar, Shubhra Ghosh;Raghunathan, Devanathan;Verma, Chandra S.
通讯作者：
Verma, Chandra S.
DOI：
10.1016/j.bbrc.2012.06.138
发表时间：
2012-07-27
影响因子：
3.1
作者：
Almerico, Anna Maria;Tutone, Marco;Lauria, Antonino
通讯作者：
Lauria, Antonino