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首页> 外文期刊>Molecular & cellular proteomics: MCP >Novel Allosteric Pathway of Eg5 Regulation Identified through Multivariate Statistical Analysis of Hydrogen-Exchange Mass Spectrometry ( HX-MS) Ligand Screening Data
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Novel Allosteric Pathway of Eg5 Regulation Identified through Multivariate Statistical Analysis of Hydrogen-Exchange Mass Spectrometry ( HX-MS) Ligand Screening Data

机译：通过多变量统计分析通过氢气交换质谱（HX-MS）配体筛选数据多元统计分析鉴定EG5调节的新型变构途径

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摘要

The mitotic kinesin Eg5 is an important target in cancer chemotherapy. A structurally diverse collection of canonical loop L5 inhibitors engage an allosteric pathway that includes elements of its microtubule binding region. However, recent evidence suggests that Eg5 may permit alternative allosteric mechanisms. Terpendole E, a natural-product Eg5 inhibitor, is active against mutants resistant to canonical loop L5 inhibitors and appears to offer a unique mode of inhibition. To investigate the variety of inhibitor responses, the structure-function properties of eighteen kinesin inhibitors were quantified with hydrogen-exchange mass spectrometry (HX-MS), functional analysis and molecular modeling. A unique strategy for high-density data analysis was implemented, based on a scalable multivariate statistical method, as current HX-MS routines have a limited capacity to guide a characterization of ligands when additional functional data is available. Inhibitor evaluation was achieved using orthogonal partial least squares projection to latent structures discriminant analysis (OPLS-DA). The strategy generated a model that identified functionally-significant conformational elements involved in kinesin inhibition, confirming the canonical allosteric pathway and identifying a novel response pathway. Terpendole E is demonstrated to be an atypical L5 site inhibitor, where binding induces an allosteric effect mediated by a destabilization in the beta-sheet core of the molecular motor, an element involved in mechanochemical coupling for structurally-related kinesins. The analysis suggests that a different approach to inhibitor development may be fruitful.
机译：有丝分裂的kinesin eg5是癌症化疗的重要靶标。结构各种各样的规范环L5抑制剂集合接合包括其微管结合区域的元素的变构途径。然而，最近的证据表明，EG5可以允许替代的渐变机制。天然产物EG5抑制剂的Terpendole E对抗典型典型型突变体的突变体似乎提供了独特的抑制模式。为了研究各种抑制剂反应，用氢气交换质谱（HX-MS），功能分析和分子建模定量了18个Kinesin抑制剂的结构功能性能。基于可伸缩的多变量统计方法实现了一种独特的高密度数据分析策略，因为当前的HX-MS例程具有有限的容量，当附加功能数据可用时引导配体的表征。使用正交部分最小二乘投影实现抑制剂评估，以潜在结构判别分析（OPLS-DA）。该策略产生了一种模型，该模型鉴定了涉及Kinesin抑制的功能性显着的构象元素，证实了规范构型途径和鉴定了一种新的反应途径。 Terpendole E被证明是一种非典型L5位点抑制剂，其中结合诱导由分子电机的β-板芯中的稳定化介导的破坏性效果，该元素参与结构相关的梭菌的机械化学偶联的元素。该分析表明，抑制剂发育的不同方法可能是富有成效的。

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