The impact of small molecule binding on the energy landscape of the intrinsically disordered protein C-myc.
The impact of small molecule binding on the energy landscape of the intrinsically disordered protein C-myc.
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DOI：
10.1371/journal.pone.0041070
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Cuchillo R
中科院分区：
文献类型：
--
作者：
Michel J;Cuchillo R
由于在几种疾病中的普遍存在，本质上无序的蛋白质是有吸引力的治疗靶点。然而，它们缺乏明确的结构，这使得寻找配体成为一项具有挑战性的任务。一个有趣的例子是癌蛋白c-Myc，它是一种在多种癌症中过度表达的转录因子。C-Myc的转录活性依赖于与伴侣蛋白Max的异源二聚作用。这种蛋白质-蛋白质相互作用被小分子10058-F4(1)破坏，该小分子与单体和无序的c-Myc结合。为了合理地解释抑制机制，利用经典力场和显式溶剂元动力学分子模拟，计算了c-Myc结构域与1结合的部分在没有和存在配体的情况下的结构系综。通过比较预测和测量的核磁共振化学位移来评估计算的结构系综的准确性。小分子1被发现扰乱载脂蛋白平衡系综的组成，并与多个不同的c-Myc构象弱结合。对apo和holo平衡系综的比较表明，c-Myc构象结合1在apo系综中已经部分形成，表明1通过扩展的构象选择机制与c-Myc结合。目前的结果对于针对内在无序蛋白质的合理配体设计工作具有重要的意义。
Intrinsically disordered proteins are attractive therapeutic targets owing to their prevalence in several diseases. Yet their lack of well-defined structure renders ligand discovery a challenging task. An intriguing example is provided by the oncoprotein c-Myc, a transcription factor that is over expressed in a broad range of cancers. Transcriptional activity of c-Myc is dependent on heterodimerization with partner protein Max. This protein-protein interaction is disrupted by the small molecule 10058-F4 (1), that binds to monomeric and disordered c-Myc. To rationalize the mechanism of inhibition, structural ensembles for the segment of the c-Myc domain that binds to 1 were computed in the absence and presence of the ligand using classical force fields and explicit solvent metadynamics molecular simulations. The accuracy of the computed structural ensembles was assessed by comparison of predicted and measured NMR chemical shifts. The small molecule 1 was found to perturb the composition of the apo equilibrium ensemble and to bind weakly to multiple distinct c-Myc conformations. Comparison of the apo and holo equilibrium ensembles reveals that the c-Myc conformations binding 1 are already partially formed in the apo ensemble, suggesting that 1 binds to c-Myc through an extended conformational selection mechanism. The present results have important implications for rational ligand design efforts targeting intrinsically disordered proteins.
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影响因子：
6.8
作者：
Dunker, A. Keith;Silman, Israel;Sussman, Joel L.
通讯作者：
Sussman, Joel L.
影响因子：
4
作者：
Dunker, A. Keith;Uversky, Vladimir N.
通讯作者：
Uversky, Vladimir N.
影响因子：
6.1
作者：
Dyson, H. Jane
通讯作者：
Dyson, H. Jane
影响因子：
16.8
作者：
Baker, Jennifer M. R.;Hudson, Rhea P.;Forman-Kay, Julie D.
通讯作者：
Forman-Kay, Julie D.
DOI：
10.1002/prot.340230412
发表时间：
1995-12-01
期刊：
PROTEINS-STRUCTURE FUNCTION AND GENETICS
影响因子：
--
作者：
Frishman, D;Argos, P
通讯作者：
Argos, P