1-(2,6-Dibenzyloxybenzoyl)-3-(9H-fluoren-9-yl)-urea: A novel cyclophilin A allosteric activator
文献类型：期刊论文
| 作者 | Lv, Maosheng2; Shi, Ting3; Mao, Xiaona2; Li, Xi2; Chen, Yingyi3; Zhu, Jin2; Ni, Shuaishuai2; Shen, Xu1,2 ; Jiang, Hualiang1,2; Li, Jian2
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| 刊名 | BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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| 出版日期 | 2012-09-07 |
| 卷号 | 425期号:4页码:938-943 |
| 关键词 | CypA PPIase activity Allosteric activator Chemical tool |
| ISSN号 | 0006-291X |
| DOI | 10.1016/j.bbrc.2012.08.014 |
| 文献子类 | Article |
| 英文摘要 | Cyclophilin A (CypA) plays an important role in many physiology processes and its overexpression has been involved in many diseases including immune disease, viral infection, neuro-degenerative disease, and cancer. However, the actual role of CypA in the diseases is still far from clear, and a complete understanding of CypA is necessary in order to direct more specific and effective therapeutic strategies. Based on the screening of our in-house library through the isomer-specific proteolysis method, we find a CypA activator (1-(2,6-Dibenzyloxybenzoyl)-3-(9H-fluoren-9-yl)-urea), compound la, which can increase CypA's PPIase activity and give allosteric behavior. The binding affinity of compound la to CypA has been confirmed by Fortebio's Octet RED system and the increased phosphorylation of ERK in H446 cells is observed by treatment with both compound la and CsA. In order to further evaluate the binding mode between the activator and CypA, the allosteric binding site and allosteric mechanism of CypA are investigated by molecular dynamics (MD) simulations in combination with mutagenesis experiments. The results show that the allosteric binding site of CypA is 7 angstrom away from its catalytic site and is composed of Cys52, His70, His54, Lys151, Thr152 and Lys155. Compound la binds to the allosteric site of CypA, stabilizing the active conformation of catalytic residues, and finally promotes the catalytic efficiency of CypA. We believe our finding of the CypA allosteric activator will be used as an effective chemical tool for further studies of CypA mechanisms in diseases. (C) 2012 Elsevier Inc. All rights reserved. |
| WOS关键词 | CIS-TRANS-ISOMERASES ; MOLECULAR-DYNAMICS ; ACCURATE DOCKING ; BINDING-PROTEIN ; RESP MODEL ; CYCLOSPORINE ; INHIBITORS ; ALGORITHM ; DATABASE ; SYSTEM |
| 资助项目 | National Natural Science Foundation of China[81102420] ; National Natural Science Foundation of China[21002028] ; National Natural Science Foundation of China[21002062] ; National S&T Major Project, China[2011ZX09102-005-02] ; Shanghai PuJiang Program[10PJ406800] ; Shanghai Committee of Science and Technology[11DZ2260600] ; Fundamental Research Funds for the Central Universities[00000000] ; Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning[00000000] |
| WOS研究方向 | Biochemistry & Molecular Biology ; Biophysics |
| 语种 | 英语 |
| WOS记录号 | WOS:000309017700041 |
| 出版者 | ACADEMIC PRESS INC ELSEVIER SCIENCE |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/277945]  |
| 专题 | 药物发现与设计中心 |
| 通讯作者 | Zhu, Jin |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China 2.E China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China; 3.Shanghai Jiao Tong Univ, Sch Med, Dept Pathophysiol, Key Lab Cell Differentiat & Apoptosis,Chinese Min, Shanghai 200025, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Lv, Maosheng,Shi, Ting,Mao, Xiaona,et al. 1-(2,6-Dibenzyloxybenzoyl)-3-(9H-fluoren-9-yl)-urea: A novel cyclophilin A allosteric activator[J]. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS,2012,425(4):938-943. |
| APA | Lv, Maosheng.,Shi, Ting.,Mao, Xiaona.,Li, Xi.,Chen, Yingyi.,...&Huang, Jin.(2012).1-(2,6-Dibenzyloxybenzoyl)-3-(9H-fluoren-9-yl)-urea: A novel cyclophilin A allosteric activator.BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS,425(4),938-943. |
| MLA | Lv, Maosheng,et al."1-(2,6-Dibenzyloxybenzoyl)-3-(9H-fluoren-9-yl)-urea: A novel cyclophilin A allosteric activator".BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 425.4(2012):938-943. |
入库方式： OAI收割
来源：上海药物研究所
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