Xiong Bin, Huang Xiao-Qin, Shen Ling-Ling, Shen Jian-Hua, Luo Xiao-Min, Shen Xu, Jiang Hua-Liang, Chen Kai-Xian
Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China.
Acta Pharmacol Sin. 2004 Jun;25(6):705-13.
Based on the structural analysis to reveal the mechanism of ligand binding to beta-secretase and the specificity of each binding sub-site.
Molecular dynamics was used to simulate on the ligand free beta-secretase and ligand bound beta-secretase. The trajectories were analyzed using the essential dynamics, and the significant conformational change was illustrated employing the DynDom program.
The essential dynamics and DynDom analyses clearly showed that the beta-secretase experienced a large conformational change upon the substrate or inhibitor binding. The flap structure adopted a swing motion, gradually covering the active site to facilitate the ligand binding process. Residues Ser86 and Ile87 served as the hinge point. Inhibitor-enzyme interaction analysis revealed that residues at P2, P1, and P1' positions of the inhibitor were very important for the binding, and residues at P2' and P3' positions may be modified to improve the binding specificity. S3 subsite of the enzyme still had space to modify the inhibitors in increasing the binding affinity.
The information presented here is valuable and could be used to identify small molecular inhibitors of beta-secretase.
基于结构分析揭示配体与β-分泌酶结合的机制以及每个结合亚位点的特异性。
利用分子动力学对无配体的β-分泌酶和结合配体的β-分泌酶进行模拟。使用主成分动力学分析轨迹，并采用DynDom程序展示显著的构象变化。
主成分动力学和DynDom分析清楚地表明，β-分泌酶在结合底物或抑制剂后经历了较大的构象变化。瓣状结构采取摆动运动，逐渐覆盖活性位点以促进配体结合过程。丝氨酸86和异亮氨酸87残基作为铰链点。抑制剂-酶相互作用分析表明，抑制剂P2、P1和P1'位置的残基对结合非常重要，P2'和P3'位置的残基可进行修饰以提高结合特异性。酶的S3亚位点在提高结合亲和力方面仍有空间对抑制剂进行修饰。
此处提供的信息很有价值，可用于鉴定β-分泌酶的小分子抑制剂。
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