X-ray structures of Torpedo californica acetylcholinesterase complexed with (+)-Huperzine A and (-)-huperzine B: Structural evidence for an active site rearrangement
文献类型：期刊论文
| 作者 | Dvir, H; Jiang, HL ; Wong, DM; Harel, M; Chetrit, M; He, XC; Jin, GY; Yu, GL; Tang, XC; Silman, I
|
| 刊名 | BIOCHEMISTRY
 |
| 出版日期 | 2002-09-03 |
| 卷号 | 41期号:35页码:10810-10818 |
| ISSN号 | 0006-2960 |
| DOI | 10.1021/bi020151 |
| 文献子类 | Article |
| 英文摘要 | Kinetic and structural data are presented on the interaction with Torpedo californica acetylcholinesterase (TcAChE) of (+)-huperzine A, a synthetic enantiomer of the anti-Alzheimer drug, (-)-huperzine A, and of its natural homologue (-)-huperzine B. (+)-Huperzine A and (-)-huperzine B bind to the enzyme with dissociation constants of 4.30 and 0.33 muM, respectively, compared to 0.18 muM for (-)-huperzine A. The X-ray structures of the complexes of (+)-huperzine A and (-)-huperzine B with TcAChE were determined to 2.1 and 2.35 Angstrom resolution, respectively, and compared to the previously determined structure of the (-)-huperzine A complex. All three interact with the "anionic" subsite of the active site, primarily through pi-pi stacking and through van der Waals or C-H...pi interactions with Trp84 and Phe330. Since their alpha-pyridone moieties are responsible for their key interactions with the active site via hydrogen bonding, and possibly via C-H...pi interactions, all three maintain similar positions and orientations with respect to it. The carbonyl oxygens of all three appear to repel the carbonyl oxygen of Gly117, thus causing the peptide bond between Gly117 and Gly118 to undergo a peptide flip. As a consequence, the position of the main chain nitrogen of Gly118 in the "oxyanion" hole in the native enzyme becomes occupied by the carbonyl of Gly117. Furthermore, the flipped conformation is stabilized by hydrogen bonding of Gly117O to Gly119N and Ala201N, the other two functional elements of the three-pronged "oxyanion hole" characteristic of cholinesterases. All three inhibitors thus would be expected to abolish hydrolysis of all ester substrates, whether charged or neutral. |
| WOS关键词 | HUPERZINE-A ; ALZHEIMERS-DISEASE ; ANTICHOLINESTERASE ACTIVITY ; CHOLINESTERASE ACTIVITY ; CEREBRAL-CORTEX ; BINDING ; MEMORY ; INHIBITION ; TACRINE ; PROTEIN |
| WOS研究方向 | Biochemistry & Molecular Biology |
| 语种 | 英语 |
| WOS记录号 | WOS:000177746300010 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/274329]  |
| 专题 | 新药研究国家重点实验室 中科院受体结构与功能重点实验室 |
| 通讯作者 | Bai, DL |
| 作者单位 | 1.Weizmann Inst Sci, Dept Neurobiol, IL-76100 Rehovot, Israel 2.Weizmann Inst Sci, Dept Biol Struct, IL-76100 Rehovot, Israel 3.Chinese Acad Sci, Shanghai Inst Biol Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 200031, Peoples R China |
| 推荐引用方式 GB/T 7714 | Dvir, H,Jiang, HL,Wong, DM,et al. X-ray structures of Torpedo californica acetylcholinesterase complexed with (+)-Huperzine A and (-)-huperzine B: Structural evidence for an active site rearrangement[J]. BIOCHEMISTRY,2002,41(35):10810-10818. |
| APA | Dvir, H.,Jiang, HL.,Wong, DM.,Harel, M.,Chetrit, M.,...&Sussman, JL.(2002).X-ray structures of Torpedo californica acetylcholinesterase complexed with (+)-Huperzine A and (-)-huperzine B: Structural evidence for an active site rearrangement.BIOCHEMISTRY,41(35),10810-10818. |
| MLA | Dvir, H,et al."X-ray structures of Torpedo californica acetylcholinesterase complexed with (+)-Huperzine A and (-)-huperzine B: Structural evidence for an active site rearrangement".BIOCHEMISTRY 41.35(2002):10810-10818. |
入库方式： OAI收割
来源：上海药物研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。