Abstract：
Alzheimer\'s disease (AD) pathogenesis has been linked to the accumulation of longer, aggregation-prone amyloid β (Aβ) peptides in the brain. Γ-secretases generate Aβ peptides from the amyloid precursor protein (APP). Γ-secretase modulators (GSMs) promote the generation of shorter, less-amyloidogenic Aβs and have therapeutic potential. However, poorly defined drug-target interactions and mechanisms of action have hampered their therapeutic development. Here, we investigate the interactions between the imidazole-based GSM and its target γ-secretase-APP using experimental and in silico approaches. We map the GSM binding site to the enzyme-substrate interface, define a drug-binding mode that is consistent with functional and structural data, and provide molecular insights into the underlying mechanisms of action. In this respect, our analyses show that occupancy of a γ-secretase (sub)pocket, mediating binding of the modulator\'s imidazole moiety, is sufficient to trigger allosteric rearrangements in γ-secretase as well as stabilize enzyme-substrate interactions. Together, these findings may facilitate the rational design of new modulators of γ-secretase with improved pharmacological properties.
摘要：
阿尔茨海默病(AD)的发病机制与积累时间较长,大脑中易聚集的淀粉样蛋白β（Aβ）肽。Γ-分泌酶从淀粉样前体蛋白(APP)产生Aβ肽。Γ-分泌酶调节剂（GSM）促进较短，淀粉样蛋白生成较少的Aβs，具有治疗潜力。然而,定义不清的药物-靶标相互作用和作用机制阻碍了它们的治疗发展.这里,我们使用实验和计算机模拟方法研究了基于咪唑的GSM及其靶标γ-分泌酶-APP之间的相互作用。我们将GSM结合位点映射到酶-底物界面，定义与功能和结构数据一致的药物结合模式，并提供对潜在作用机制的分子见解。在这方面,我们的分析表明，γ-分泌酶(子)口袋的占用，介导调节剂的咪唑部分的结合，足以触发γ-分泌酶的变构重排以及稳定酶-底物相互作用。一起,这些发现可能有助于合理设计具有改善药理特性的γ-分泌酶新调节剂。
