An inhibitor binding pocket distinct from the catalytic active site on human β-APP cleaving enzyme
An inhibitor binding pocket distinct from the catalytic active site on human β-APP cleaving enzyme
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DOI：
10.1021/bi050932l
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发表时间：
2005-08-30
期刊：
影响因子：
2.9
通讯作者：
Copeland, RA
中科院分区：
文献类型：
--
作者：
Kornacker, MG;Lai, ZH;Copeland, RA
β -APP切割酶（BACE）负责APP蛋白的两种蛋白水解裂解中的第一种，这两种蛋白水解裂解共同导致阿尔茨海默病相关A -肽的产生。人们普遍认为，通过抑制BACE来停止β肽的产生，是治疗阿尔茨海默病的一种有吸引力的治疗方式。BACE是一种天冬氨酸蛋白酶，在药学界应用传统的设计方法来开发这种酶的活性位点定向抑制剂有很大的努力。我们在这里报告了在BACE的催化结构域中发现的与酶活性位点（即外源位点）不同的配体结合袋。肽最初是从组合噬菌体肽库中鉴定出来的，含有YPYF(I/ L)P（L/I）序列，即使在活性位点导向抑制剂达到饱和浓度的情况下，也能特异性地与该外源位点结合。肽与BACE外源结合导致app相关的BACE蛋白基底物的蛋白水解受到浓度依赖性抑制。这种外源位点的发现为鉴定和开发新的潜在选择性BACE小分子抑制剂提供了新的机会，这些抑制剂通过外源位点而不是活性位点结合相互作用起作用。
beta-APP cleaving enzyme (BACE) is responsible for the first of two proteolytic cleavages of the APP protein that together lead to the generation of the Alzheimer's disease-associated A beta peptide. It is widely believed that halting the production of A beta peptide, by inhibition of BACE, is an attractive therapeutic modality for the treatment of Alzheimer's disease. BACE is an aspartyl protease, and there is significant effort in the pharmaceutical community to apply traditional design methods to the development of active site-directed inhibitors of this enzyme. We report here the discovery of a ligand binding pocket within the catalytic domain of BACE that is distinct from the enzymatic active site (i.e., an exosite). Peptides, initially identified from combinatorial phage peptide libraries, contain the sequence YPYF(I/ L)P(L/I) and bind specifically to this exosite, even in the presence of saturating concentrations of active site-directed inhibitors. Binding of peptides to the BACE exosite leads to a concentration-dependent inhibition of proteolysis for APP-related, protein-based substrates of BACE. The discovery of this exosite opens new opportunities for the identification and development of novel and potentially selective small molecule inhibitors of BACE that act through exosite, rather than active site, binding interactions.