The impact of crystallization conditions on structure-based drug design: A case study on the methylene blue/acetylcholinesterase complex
文献类型：期刊论文
| 作者 | Dym, Orly2,6; Song, Wanling5; Felder, Clifford4; Roth, Esther3; Shnyrov, Valery7; Ashani, Yacov4; Xu, Yechun5 ; Joosten, Robbie P.8; Weiner, Lev1; Sussman, Joel L.2,4
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| 刊名 | PROTEIN SCIENCE
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| 出版日期 | 2016-06 |
| 卷号 | 25期号:6页码:1096-1114 |
| 关键词 | polyethylene glycol structure-based drug discovery acetylcholinesterase methylene blue decamethonium |
| ISSN号 | 0961-8368 |
| DOI | 10.1002/pro.2923 |
| 文献子类 | Article |
| 英文摘要 | Structure-based drug design utilizes apoprotein or complex structures retrieved from the PDB. >57% of crystallographic PDB entries were obtained with polyethylene glycols (PEGs) as precipitant and/or as cryoprotectant, but <6% of these report presence of individual ethyleneglycol oligomers. We report a case in which ethyleneglycol oligomers' presence in a crystal structure markedly affected the bound ligand's position. Specifically, we compared the positions of methylene blue and decamethonium in acetylcholinesterase complexes obtained using isomorphous crystals precipitated with PEG200 or ammonium sulfate. The ligands' positions within the active-site gorge in complexes obtained using PEG200 are influenced by presence of ethyleneglycol oligomers in both cases bound to W84 at the gorge's bottom, preventing interaction of the ligand's proximal quaternary group with its indole. Consequently, both ligands are similar to 3.0 angstrom further up the gorge than in complexes obtained using crystals precipitated with ammonium sulfate, in which the quaternary groups make direct p-cation interactions with the indole. These findings have implications for structure-based drug design, since data for ligand-protein complexes with polyethylene glycol as precipitant may not reflect the ligand's position in its absence, and could result in selecting incorrect drug discovery leads. Docking methylene blue into the structure obtained with PEG200, but omitting the ethyleneglycols, yields results agreeing poorly with the crystal structure; excellent agreement is obtained if they are included. Many proteins display features in which precipitants might lodge. It will be important to investigate presence of precipitants in published crystal structures, and whether it has resulted in misinterpreting electron density maps, adversely affecting drug design. |
| WOS关键词 | TORPEDO-CALIFORNICA ACETYLCHOLINESTERASE ; DIFFERENTIAL SCANNING CALORIMETRY ; ACTIVE-SITE GORGE ; PERIPHERAL ANIONIC SITE ; ALZHEIMERS-DISEASE ; CRYSTAL-STRUCTURES ; TARGETED OXIDATION ; AUTOMATED DOCKING ; GENETIC ALGORITHM ; ACCURATE DOCKING |
| 资助项目 | I-CORE Program of the Planning and Budgeting Committee[00000000] ; Israel Science Foundation[1775/12] ; Vidi (Netherlands Organisation for Scientific Research[NOW] |
| WOS研究方向 | Biochemistry & Molecular Biology |
| 语种 | 英语 |
| WOS记录号 | WOS:000380045600002 |
| 出版者 | WILEY |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/276010]  |
| 专题 | 药物发现与设计中心 |
| 通讯作者 | Silman, Israel |
| 作者单位 | 1.Weizmann Inst Sci, Dept Chem Res Support, IL-76100 Rehovot, Israel 2.Weizmann Inst Sci, Israel Struct Prote Ctr, IL-76100 Rehovot, Israel; 3.Weizmann Inst Sci, Dept Neurobiol, IL-76100 Rehovot, Israel; 4.Weizmann Inst Sci, Dept Biol Struct, IL-76100 Rehovot, Israel; 5.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, CAS Key Lab Receptor Res, Shanghai 22, Peoples R China; 6.Weizmann Inst Sci, Dept Biol Chem, IL-76100 Rehovot, Israel; 7.Univ Salamanca, Dept Biochem & Mol Biol, Salamanca 37007, Spain; 8.Netherlands Canc Inst, Dept Biochem, NL-1066 CX Amsterdam, Netherlands; |
| 推荐引用方式 GB/T 7714 | Dym, Orly,Song, Wanling,Felder, Clifford,et al. The impact of crystallization conditions on structure-based drug design: A case study on the methylene blue/acetylcholinesterase complex[J]. PROTEIN SCIENCE,2016,25(6):1096-1114. |
| APA | Dym, Orly.,Song, Wanling.,Felder, Clifford.,Roth, Esther.,Shnyrov, Valery.,...&Silman, Israel.(2016).The impact of crystallization conditions on structure-based drug design: A case study on the methylene blue/acetylcholinesterase complex.PROTEIN SCIENCE,25(6),1096-1114. |
| MLA | Dym, Orly,et al."The impact of crystallization conditions on structure-based drug design: A case study on the methylene blue/acetylcholinesterase complex".PROTEIN SCIENCE 25.6(2016):1096-1114. |
入库方式： OAI收割
来源：上海药物研究所
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