Institute for Biophysical Chemistry, Hannover Medical School, 30625 Hannover,
J Med Chem. 2011 Jun 9;54(11):3675-85. doi: 10.1021/jm200259f. Epub 2011 May 13.
Myosin activity is crucial for many biological functions. Strong links have been established between changes in the activity of specific myosin isoforms and diseases such as cancer, cardiovascular failure, and disorders of sensory organs and the central nervous system. The modulation of specific myosin isoforms therefore holds a strong therapeutic potential. In recent work, we identified members of the marine alkaloid family of pseudilins as potent inhibitors of myosin-dependent processes. Here, we report the crystal structure of the complex between the Dictyostelium myosin 2 motor domain and 2,4-dichloro-6-(3,4,5-tribromo-1H-pyrrole-2-yl)phenol (3). Detailed comparison with previously solved structures of the myosin 2 complex with bound pentabromopseudilin (2a) or pentachloropseudilin (4a) provides insights into the molecular basis of the allosteric communication between the catalytic and the allosteric sites. Moreover, we describe the inhibitory potency for a congeneric series of halogenated pseudilins. Insight into their mode of action is gained by applying a combination of experimental and computational approaches.
肌球蛋白的活性对许多生物功能至关重要。特定肌球蛋白同工型活性的变化与癌症、心血管衰竭以及感觉器官和中枢神经系统紊乱等疾病之间存在着紧密的联系。因此，特定肌球蛋白同工型的调节具有很强的治疗潜力。在最近的工作中，我们发现海洋生物碱假木贼碱家族的成员是肌球蛋白依赖性过程的有效抑制剂。在这里，我们报告了 Dictyostelium 肌球蛋白 2 马达结构域与 2,4-二氯-6-(3,4,5-三溴-1H-吡咯-2-基)苯酚（3）复合物的晶体结构。与先前解决的肌球蛋白 2 与结合的五溴假木贼碱（2a）或五氯假木贼碱（4a）复合物的结构的详细比较提供了对催化和变构位点之间的变构通讯的分子基础的深入了解。此外，我们描述了同类系列卤代假木贼碱的抑制效力。通过应用实验和计算方法的组合，获得了对其作用模式的了解。
