Gianti Eleonora, Zauhar Randy J
Department of Chemistry and Biochemistry, University of the Sciences, 600 S. 43rd Street, Philadelphia, PA, 19104, USA,
J Comput Aided Mol Des. 2015 May;29(5):451-70. doi: 10.1007/s10822-015-9835-6. Epub 2015 Mar 10.
The signal transducer and activator of transcription 5 (STAT5) is a member of the STAT family of proteins, implicated in cell growth and differentiation. STAT activation is regulated by phosphorylation of protein monomers at conserved tyrosine residues, followed by binding to phospho-peptide pockets and subsequent dimerization. STAT5 is implicated in the development of severe pathological conditions, including many cancer forms. However, nowadays a few STAT5 inhibitors are known, and only one crystal structure of the inactive STAT5 dimer is publicly available. With a view to enabling structure-based drug design, we have: (1) analyzed phospho-peptide binding pockets on SH2 domains of STAT5, STAT1 and STAT3; (2) generated a model of STAT5 bound to phospho-peptides; (3) assessed our model by docking against a class of known STAT5 inhibitors (Müller et al. in ChemBioChem 9:723-727, 2008); (4) used molecular dynamics simulations to optimize the molecular determinants responsible for binding and (5) proposed unique "Binding Signatures" of STAT5. Our results put in place the foundations to address STAT5 as a target for rational drug design, from sequence, structural and functional perspectives.
信号转导及转录激活因子5（STAT5）是STAT蛋白家族的成员之一，与细胞生长和分化有关。STAT的激活通过蛋白单体在保守酪氨酸残基处的磷酸化来调节，随后与磷酸肽口袋结合并随后二聚化。STAT5与包括多种癌症形式在内的严重病理状况的发展有关。然而，目前已知的STAT5抑制剂很少，并且只有非活性STAT5二聚体的一种晶体结构是公开可用的。为了实现基于结构的药物设计，我们进行了以下工作：（1）分析了STAT5、STAT1和STAT3的SH2结构域上的磷酸肽结合口袋；（2）生成了与磷酸肽结合的STAT5模型；（3）通过与一类已知的STAT5抑制剂对接来评估我们的模型（Müller等人，《化学生物化学》9：723 - 727，2008年）；（4）使用分子动力学模拟来优化负责结合的分子决定因素；（5）提出了STAT5独特的“结合特征”。我们的结果从序列、结构和功能的角度为将STAT5作为合理药物设计的靶点奠定了基础。
