BACE X-RAY STRUCTURE STUDIES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 含抑制剂复合体的重组人β-分泌酶(BACE)晶体结构 β-分泌酶(BACE)是一种膜结合的天冬氨酸蛋白酶，它能裂解淀粉样前体蛋白生成淀粉样β蛋白(Ab)的N-末端。B-分泌酶已被认为是抗淀粉样蛋白治疗阿尔茨海默病-S病的一个很好的靶点。寻找b-分泌酶的抑制剂是阿尔茨海默病-S病药物开发的主要目标之一。 我们使用的重组BACE蛋白在大肠杆菌中表达，然后复性和纯化，以生长与内部抑制物共晶体。这些晶体将使用X射线光束线进行研究，如APS的那些，以获得衍射数据，这些数据将被分析以获得结构信息，以加强我们的药物发现工作。 参考文献 1.Hardy，J.和Selkoe，D.J.，Science，297,353-356(2002)。 2.Searman，M.S.等人，《生物化学》，39,8698-8704(2000)。 3.李永明等人，Proc.纳特。阿卡德。SCI。美国，97,6138-6143(2000)。 4.李宇明等，《自然》，2000年版，第405、689-694页。 5.田刚等人，J.Biol.化学，2002年，第277,31499-31505页。 6.Hong L.等人，《科学》，290,150-153(2000)

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Recombinant human beta-secretase (BACE)crystal structures in complex with inhibitors Beta-Secretase (BACE) is a membrane-bound aspartyl protease that cleaves the amyloid precursor protein to generate the N-terminus of the amyloid beta (ab) peptide. b-Secretase has been implicated to be an excellent target for anti-amyloid therapy for the treatment of Alzheimer?s disease. Finding inhibitors of b-secretase is one of the major goals of Alzheimer?s disease drug development. The recombinant BACE proteins we used were expressed in E coli and subsequently refolded and purified to grow co-crystals with in-house inhibitors. The crystals will be studied using X-ray beamlines, like those at APS, to get diffraction data, which will be analyzed for structural information to enhance our drug discovery efforts. References 1. Hardy, J. and Selkoe, D.J., Science, 297, 353-356 (2002). 2. Shearman, M.S., et al., Biochemistry, 39, 8698-8704 (2000). 3. Li, Y-M., et al., Proc. Nat. Acad. Sci. USA, 97, 6138-6143 (2000). 4. Li, Y-M., et al., Nature, 405, 689-694 (2000). 5. Tian G., et al., J. Biol. Chem., 277, 31499-31505 (2002). 6. Hong, L., et al., Science 290, 150-153(2000)