Klein Tobias, Tucker Julie, Holdgate Geoffrey A, Norman Richard A, Breeze Alexander L
Discovery Sciences, AstraZeneca R&D , Alderley Park, Macclesfield, Cheshire, SK10 4TG, U.K.
ACS Med Chem Lett. 2013 Dec 6;5(2):166-71. doi: 10.1021/ml4004205. eCollection 2014 Feb 13.
The binding of a ligand to its target protein is often accompanied by conformational changes of both the protein and the ligand. This is of particular interest, since structural rearrangements of the macromolecular target and the ligand influence the free energy change upon complex formation. In this study, we use X-ray crystallography, isothermal titration calorimetry, and surface-plasmon resonance biosensor analysis to investigate the binding of pyrazolylaminopyrimidine inhibitors to FGFR1 tyrosine kinase, an important anticancer target. Our results highlight that structurally close analogs of this inhibitor series interact with FGFR1 with different binding modes, which are a consequence of conformational changes in both the protein and the ligand as well as the bound water network. Together with the collected kinetic and thermodynamic data, we use the protein-ligand crystal structure information to rationalize the observed inhibitory potencies on a molecular level.
配体与其靶蛋白的结合通常伴随着蛋白和配体的构象变化。这一点尤其令人关注，因为大分子靶标和配体的结构重排会影响复合物形成时的自由能变化。在本研究中，我们使用X射线晶体学、等温滴定量热法和表面等离子体共振生物传感器分析来研究吡唑基氨基嘧啶抑制剂与FGFR1酪氨酸激酶（一种重要的抗癌靶标）的结合。我们的结果突出表明，该抑制剂系列中结构相近的类似物以不同的结合模式与FGFR1相互作用，这是蛋白、配体以及结合水网络构象变化的结果。结合收集到的动力学和热力学数据，我们利用蛋白质-配体晶体结构信息在分子水平上对观察到的抑制效力进行合理化解释。
