Tolia Alexandra, De Strooper Bart
Center for Human Genetics, KULeuven and Department for Developmental and Molecular Genetics, VIB, Herestraat 49, 3000 Leuven, Belgium.
Semin Cell Dev Biol. 2009 Apr;20(2):211-8. doi: 10.1016/j.semcdb.2008.10.007. Epub 2008 Nov 1.
The gamma-secretase complex is a prime target for pharmacological intervention in Alzheimer's disease and so far drug discovery efforts have yielded a large variety of potent and rather specific inhibitors of this enzymatic activity. However, as gamma-secretase is able to cleave a wide variety of physiological important substrates, the real challenge is to develop substrate-specific compounds. Therefore, obtaining structural information about gamma-secretase is indispensable. As crystal structures of the complex will be difficult to achieve, applied biochemical approaches need to be integrated with structural information obtained from other intramembrane-cleaving proteases. Here we review current knowledge about the structure and function of gamma-secretase and discuss the value of these findings for the mechanistic understanding of this unusual protease.
γ-分泌酶复合物是阿尔茨海默病药物干预的主要靶点，迄今为止，药物研发工作已产生了多种针对该酶活性的强效且相当特异的抑制剂。然而，由于γ-分泌酶能够切割多种生理上重要的底物，真正的挑战在于开发底物特异性化合物。因此，获取有关γ-分泌酶的结构信息是必不可少的。由于该复合物的晶体结构难以获得，应用的生化方法需要与从其他膜内切割蛋白酶获得的结构信息相结合。在此，我们综述了目前关于γ-分泌酶结构和功能的知识，并讨论了这些发现对于理解这种特殊蛋白酶机制的价值。
