Binding modes of peptidomimetics designed to inhibit STAT3.
Binding modes of peptidomimetics designed to inhibit STAT3.
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DOI：
10.1371/journal.pone.0051603
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Kavraki LE
中科院分区：
文献类型：
--
作者：
Dhanik A;McMurray JS;Kavraki LE
STAT 3是一种转录因子，已发现其在许多人类癌症中被组成性激活。STAT 3通过其SH 2结构域的二聚化和二聚体随后易位到细胞核导致抗凋亡基因的转录。因此，防止二聚化是抑制STAT 3活性的有吸引力的策略。基于磷酸酪氨酸的肽模拟物抑制剂，其模拟pTyr-Xaa-Yaa-Gln基序并且具有强至弱的结合亲和力，先前已被研究。众所周知，蛋白质-抑制剂复合物的结构对于理解结合相互作用和设计更强的抑制剂是重要的。然而，与STAT 3的SH 2结构域结合的抑制剂的实验结构是不可用的。在本文中，我们描述了一个计算研究，结合分子对接和分子动力学模型结构的12个拟肽抑制剂绑定到SH 2结构域的STAT 3。对模型结构进行了详细分析，以评估结合相互作用的特征。我们还估计结合MMPB/GBSA为基础的能量和熵结合成本的抑制剂的结合亲和力。估计的亲和力与实验获得的亲和力密切相关。建模结果表明，结合模式是一致的，与有限的先前的建模研究涉及SH 2结构域和磷酸酪氨酸（pTyr）为基础的抑制剂的结合相互作用。我们还发现了一种稳定的新型结合模式，该模式涉及SH 2结构域的两个环的变形，该变形随后掩埋了一种更强抑制剂的C末端。这种新的结合模式可以证明有助于开发更有效的抑制剂，旨在防止癌症靶蛋白STAT 3的二聚化。
STAT3 is a transcription factor that has been found to be constitutively activated in a number of human cancers. Dimerization of STAT3 via its SH2 domain and the subsequent translocation of the dimer to the nucleus leads to transcription of anti-apoptotic genes. Prevention of the dimerization is thus an attractive strategy for inhibiting the activity of STAT3. Phosphotyrosine-based peptidomimetic inhibitors, which mimic pTyr-Xaa-Yaa-Gln motif and have strong to weak binding affinities, have been previously investigated. It is well-known that structures of protein-inhibitor complexes are important for understanding the binding interactions and designing stronger inhibitors. Experimental structures of inhibitors bound to the SH2 domain of STAT3 are, however, unavailable. In this paper we describe a computational study that combined molecular docking and molecular dynamics to model structures of 12 peptidomimetic inhibitors bound to the SH2 domain of STAT3. A detailed analysis of the modeled structures was performed to evaluate the characteristics of the binding interactions. We also estimated the binding affinities of the inhibitors by combining MMPB/GBSA-based energies and entropic cost of binding. The estimated affinities correlate strongly with the experimentally obtained affinities. Modeling results show binding modes that are consistent with limited previous modeling studies on binding interactions involving the SH2 domain and phosphotyrosine(pTyr)-based inhibitors. We also discovered a stable novel binding mode that involves deformation of two loops of the SH2 domain that subsequently bury the C-terminal end of one of the stronger inhibitors. The novel binding mode could prove useful for developing more potent inhibitors aimed at preventing dimerization of cancer target protein STAT3.
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