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DOI | 10.1038/s41467-018-05610-w |
Revealing the mechanism for covalent inhibition of glycoside hydrolases by carbasugars at an atomic level | |
Ren, Weiwu1; Pengelly, Robert2; Farren-Dai, Marco1; Abadi, Saeideh Shamsi Kazem3; Oehler, Verena2; Akintola, Oluwafemi1; Draper, Jason1; Meanwell, Michael1; Chakladar, Saswati1; Swiderek, Katarzyna4; Moliner, Vicent4; Britton, Robert1; Gloster, Tracey M.3; Bennet, Andrew J.1 | |
2018-08-13 | |
发表期刊 | NATURE COMMUNICATIONS
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ISSN | 2041-1723 |
出版年 | 2018 |
卷号 | 9 |
文章类型 | Article |
语种 | 英语 |
国家 | Canada; Scotland; Spain |
英文摘要 | Mechanism-based glycoside hydrolase inhibitors are carbohydrate analogs that mimic the natural substrate's structure. Their covalent bond formation with the glycoside hydrolase makes these compounds excellent tools for chemical biology and potential drug candidates. Here we report the synthesis of cyclohexene-based a-galactopyranoside mimics and the kinetic and structural characterization of their inhibitory activity toward an a-galactosidase from Thermotoga maritima (TmGalA). By solving the structures of several enzyme-bound species during mechanism-based covalent inhibition of TmGalA, we show that the Michaelis complexes for intact inhibitor and product have half-chair (H-2(3)) conformations for the cyclohexene fragment, while the covalently linked intermediate adopts a flattened half-chair (H-2(3)) conformation. Hybrid QM/MM calculations confirm the structural and electronic properties of the enzyme-bound species and provide insight into key interactions in the enzyme-active site. These insights should stimulate the design of mechanism-based glycoside hydrolase inhibitors with tailored chemical properties. |
领域 | 资源环境 |
收录类别 | SCI-E |
WOS记录号 | WOS:000441382000021 |
WOS关键词 | GLUCOSIDASE INHIBITORS ; ALPHA-GALACTOSIDASE ; POTENTIAL FUNCTIONS ; METATHESIS ; HYDROLYSIS ; ALDEHYDES ; CATALYSTS ; CRYSTALLOGRAPHY ; OPTIMIZATION ; FLUORINATION |
WOS类目 | Multidisciplinary Sciences |
WOS研究方向 | Science & Technology - Other Topics |
URL | 查看原文 |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | http://119.78.100.173/C666/handle/2XK7JSWQ/203932 |
专题 | 资源环境科学 |
作者单位 | 1.Simon Fraser Univ, Dept Chem, 8888 Univ Dr, Burnaby, BC V5A 1S6, Canada; 2.Univ St Andrews, Biomed Sci Res Complex, St Andrews KY16 9ST, Fife, Scotland; 3.Simon Fraser Univ, Dept Mol Biol & Biochem, 8888 Univ Dr, Burnaby, BC V5A 1S6, Canada; 4.Univ Jaume 1, Dept Quim Fis & Analit, Castellon de La Plana 12071, Spain |
推荐引用方式 GB/T 7714 | Ren, Weiwu,Pengelly, Robert,Farren-Dai, Marco,et al. Revealing the mechanism for covalent inhibition of glycoside hydrolases by carbasugars at an atomic level[J]. NATURE COMMUNICATIONS,2018,9. |
APA | Ren, Weiwu.,Pengelly, Robert.,Farren-Dai, Marco.,Abadi, Saeideh Shamsi Kazem.,Oehler, Verena.,...&Bennet, Andrew J..(2018).Revealing the mechanism for covalent inhibition of glycoside hydrolases by carbasugars at an atomic level.NATURE COMMUNICATIONS,9. |
MLA | Ren, Weiwu,et al."Revealing the mechanism for covalent inhibition of glycoside hydrolases by carbasugars at an atomic level".NATURE COMMUNICATIONS 9(2018). |
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