Crystal structure of memapsin 2 (β-secretase) in complex with an inhibitor OM00-3
Crystal structure of memapsin 2 (β-secretase) in complex with an inhibitor OM00-3
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DOI：
10.1021/bi026232n
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发表时间：
2002-09-10
期刊：
影响因子：
2.9
通讯作者：
Tang, J
中科院分区：
文献类型：
--
作者：
Hong, L;Turner, RT;Tang, J
已在2.1埃分辨率下测定了与抑制剂OM 00 -3（Glu-Leu-Asp-Leu*Ala-Val-Glu-Phe，Ki = 0.3 nM，星号表示羟脯氨酸过渡态电子等排体）结合的人膜蛋白酶2的催化结构域的结构。在结构中唯一定义的是S-3'和S-4'亚位点的位置，其在与抑制剂OM 99 -2复合的膜蛋白酶2的先前结构中未被鉴定（Glu-Val-Asn-Leu*Ala-Ala-Glu-Phe，Ki = InM）。还观察到P-2和P-4侧链的不同结合模式。这些新的结构元件对于设计新的抑制剂是有用的。结构和动力学数据表明，用OM 00 -3中的缬氨酸替换OM 99 -2中的P-2'丙氨酸稳定了P-3'和P-4 '的结合。
The structure of the catalytic domain of human memapsin 2 bound to an inhibitor OM00-3 (Glu-Leu-Asp-Leu*Ala-Val-Glu-Phe, K-i = 0.3 nM, the asterisk denotes the hydroxyethylene transition-state isostere) has been determined at 2.1 Angstrom resolution. Uniquely defined in the structure are the locations of S-3' and S-4' subsites, which were not identified in the previous structure of memapsin 2 in complex with the inhibitor OM99-2 (Glu-Val-Asn-Leu*Ala-Ala-Glu-Phe, Ki = I nM). Different binding modes for the P-2 and P-4 side chains are also observed. These new structural elements are useful for the design of new inhibitors. The structural and kinetic data indicate that the replacement of the P-2' alanine in OM99-2 with a valine in OM00-3 stabilizes the binding of P-3' and P-4'.