Langenfeld Florent, Guarracino Yann, Arock Michel, Trouvé Alain, Tchertanov Luba
Laboratoire de Biologie et Pharmacologie Appliquée Ecole Normale Supérieure de Cachan, CNRS, Université Paris-Saclay, Cachan, France.
Centre de Mathématiques et de Leurs applications, Ecole Normale Supérieure de Cachan, CNRS, Université Paris-Saclay, Cachan, France.
PLoS One. 2015 Dec 30;10(12):e0145142. doi: 10.1371/journal.pone.0145142. eCollection 2015.
Signal Transducer and Activator of Transcription STAT5 is a key mediator of cell proliferation, differentiation and survival. While STAT5 activity is tightly regulated in normal cells, its constitutive activation directly contributes to oncogenesis and is associated with a broad range of hematological and solid tumor cancers. Therefore the development of compounds able to modulate pathogenic activation of this protein is a very challenging endeavor. A crucial step of drug design is the understanding of the protein conformational features and the definition of putative binding site(s) for such modulators. Currently, there is no structural data available for human STAT5 and our study is the first footprint towards the description of structure and dynamics of this protein. We investigated structural and dynamical features of the two STAT5 isoforms, STAT5a and STAT5b, taken into account their phosphorylation status. The study was based on the exploration of molecular dynamics simulations by different analytical methods. Despite the overall folding similarity of STAT5 proteins, the MD conformations display specific structural and dynamical features for each protein, indicating first, sequence-encoded structural properties and second, phosphorylation-induced effects which contribute to local and long-distance structural rearrangements interpreted as allosteric event. Further examination of the dynamical coupling between distant sites provides evidence for alternative profiles of the communication pathways inside and between the STAT5 domains. These results add a new insight to the understanding of the crucial role of intrinsic molecular dynamics in mediating intramolecular signaling in STAT5. Two pockets, localized in close proximity to the phosphotyrosine-binding site and adjacent to the channel for communication pathways across STAT5, may constitute valid targets to develop inhibitors able to modulate the function-related communication properties of this signaling protein.
信号转导子和转录激活子STAT5是细胞增殖、分化和存活的关键调节因子。虽然STAT5的活性在正常细胞中受到严格调控，但其组成型激活直接促进肿瘤发生，并与多种血液系统和实体肿瘤相关。因此，开发能够调节该蛋白致病性激活的化合物是一项极具挑战性的工作。药物设计的关键步骤是了解蛋白质的构象特征以及此类调节剂假定结合位点的定义。目前，尚无人类STAT5的结构数据，我们的研究是描述该蛋白结构和动力学的第一步。我们研究了两种STAT5亚型STAT5a和STAT5b的结构和动力学特征，并考虑了它们的磷酸化状态。该研究基于通过不同分析方法对分子动力学模拟的探索。尽管STAT5蛋白的整体折叠相似，但分子动力学构象对每种蛋白都显示出特定的结构和动力学特征，这首先表明了序列编码的结构特性，其次表明了磷酸化诱导的效应，这些效应导致局部和长距离的结构重排，被解释为变构事件。对远距离位点之间动态耦合的进一步研究为STAT5结构域内部和之间通信途径的替代模式提供了证据。这些结果为理解内在分子动力学在介导STAT5分子内信号传导中的关键作用提供了新的见解。两个口袋位于靠近磷酸酪氨酸结合位点且与贯穿STAT5的通信途径通道相邻的位置，可能构成开发能够调节这种信号蛋白功能相关通信特性的抑制剂的有效靶点。
