Rational redesign of inhibitors of furin/kexin processing proteases
文献类型：期刊论文
| 作者 | Ye, YZ; Fei, H; Ding, DF |
| 刊名 | ACTA BIOCHIMICA ET BIOPHYSICA SINICA
 |
| 出版日期 | 2001 |
| 卷号 | 33期号:5页码:504-512 |
| 关键词 | homology modeling weighted evolutionary tracing interface redesign processing proteases eglin C |
| 通讯作者 | , |
| 英文摘要 | Furin/kexin processing proteases catalyze the proteolysis of large protein precursors involved in many biological processes, such as zymogen activation, peptide hormone synthesis, viral protein processing and receptor maturation, making them potential targets for therapeutic agents. Herein, homology modeling and weighted evolutionary tracing were combined to investigate the interaction mechanism of furin/kex2 with eglin C mutants. The model structures showed that there were many acidic residues in the furin (kex2) binding interface, contributing to specificity for multiple basic residues of their corresponding substrates or inhibitors. Besides, some rational explanations were presented for the different inhibitor/substrate specificity of the furin/kexin members by combining the model structures with results of evolutionary tracing. Based on these analyses, an attempt was made to rationally redesign the eglin C by interface engineering with heterogeneous self-consistent ensemble optimization to improve its inhibitory specificity on furin/kex2. With the model complex structures of furin/kex2 and eglin C variants as structural templates, the P-1, P-2 and P-4 of eglin C were redesigned, respectively. The design results show that both furin and kex2 favored basic residues at P-1, P-2 and P-4 in eglin C, in good agreement with the experimental data. The detection of many specific residues in S' part of furin/kexin sequences made possible designing inhibitors with high specific binding to furin and kex2, respectively. As for furin, the best inhibitor designed was eglin C-P-2'Glu-P-3'Asp-P-4'Arg (only these three positions were shown), while the best eglin C variant for kex2 designed was P-2'Arg-P-3'Arg-P-4'Glu. The structures show that furin and kex2 form distinct interactions with these two eglin C variants. Herein, a strategy was proposed that combine homology modeling, evolutionary tracing and rational interface redesign to investigate enzyme-inhibitor interactions and inhibitor engineering. This computational design gives some rational guidance to further experimental inhibitor engineering. |
| 学科主题 | Biochemistry & Molecular Biology; Biophysics |
| 类目[WOS] | Biochemistry & Molecular Biology ; Biophysics |
| 关键词[WOS] | PROPROTEIN CONVERTASES ; SERINE PROTEASES ; SIDE-CHAIN ; SPECIFICITY ; LIBRARY ; PROTEIN ; FURIN ; DESIGN |
| 收录类别 | SCI |
| 语种 | 中文 |
| WOS记录号 | WOS:000171403600006 |
| 版本 | 出版稿 |
| 源URL | [http://202.127.25.143/handle/331003/2667]  |
| 专题 | 上海生化细胞研究所_上海生科院生化细胞研究所 |
| 推荐引用方式 GB/T 7714 | Ye, YZ,Fei, H,Ding, DF. Rational redesign of inhibitors of furin/kexin processing proteases[J]. ACTA BIOCHIMICA ET BIOPHYSICA SINICA,2001,33(5):504-512. |
| APA | Ye, YZ,Fei, H,&Ding, DF.(2001).Rational redesign of inhibitors of furin/kexin processing proteases.ACTA BIOCHIMICA ET BIOPHYSICA SINICA,33(5),504-512. |
| MLA | Ye, YZ,et al."Rational redesign of inhibitors of furin/kexin processing proteases".ACTA BIOCHIMICA ET BIOPHYSICA SINICA 33.5(2001):504-512. |
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