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DOI | 10.1038/s41467-017-02273-x |
Structure and inhibition mechanism of the catalytic domain of human squalene epoxidase | |
Padyana, Anil K.1; Gross, Stefan1; Jin, Lei2; Cianchetta, Giovanni1,5; Narayanaswamy, Rohini1; Wang, Feng3; Wang, Rui3,6; Fang, Cheng4; Lv, Xiaobing4,7; Biiler, Scott A.1; Dang, Lenny1; Mahoney, Christopher E.1; Nagaraja, Nelamangala1; Pirman, David1; Sui, Zhihua1; Popovici-Muller, Janeta1,8; Smolen, Gromoslaw A.1,9 | |
2019-01-09 | |
发表期刊 | NATURE COMMUNICATIONS
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ISSN | 2041-1723 |
出版年 | 2019 |
卷号 | 10 |
文章类型 | Article |
语种 | 英语 |
国家 | USA; Peoples R China |
英文摘要 | Squalene epoxidase (SQLE), also known as squalene monooxygenase, catalyzes the stereospecific conversion of squalene to 2,3(S)-oxidosqualene, a key step in cholesterol biosynthesis. SQLE inhibition is targeted for the treatment of hypercholesteremia, cancer, and fungal infections. However, lack of structure-function understanding has hindered further progression of its inhibitors. We have determined the first three-dimensional high-resolution crystal structures of human SQLE catalytic domain with small molecule inhibitors (2.3 angstrom and 2.5 angstrom). Comparison with its unliganded state (3.0 angstrom) reveals conformational rearrangements upon inhibitor binding, thus allowing deeper interpretation of known structure-activity relationships. We use the human SQLE structure to further understand the specificity of terbinafine, an approved agent targeting fungal SQLE, and to provide the structural insights into terbinafine-resistant mutants encountered in the clinic. Collectively, these findings elucidate the structural basis for the specificity of the epoxidation reaction catalyzed by SQLE and enable further rational development of next-generation inhibitors. |
领域 | 资源环境 |
收录类别 | SCI-E |
WOS记录号 | WOS:000455264100009 |
WOS关键词 | CHOLESTEROL-SYNTHESIS ; TERBINAFINE RESISTANCE ; MONOOXYGENASE ; REDUCTASE ; DEGRADATION ; FEATURES ; TARGET ; ENZYME ; NB-598 ; POINT |
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/203593 |
专题 | 资源环境科学 |
作者单位 | 1.Agios Pharmaceut, 88 Sidney St, Cambridge, MA 02139 USA; 2.Agile Biostruct Solut Consulting LLC, 8 Harris Ave, Wellesley, MA 02481 USA; 3.Wuxi Biortus Biosci Co Ltd, 6 Dongsheng West Rd, Jiangyin 214437, Peoples R China; 4.Shanghai ChemPartner Co Ltd, 998 Halei Rd, Shanghai 201203, Peoples R China; 5.KSQ Therapeut, 610 Main St, Cambridge, MA 02139 USA; 6.Xiamen Univ, Dept Stomatol, Xiamen 361102, Peoples R China; 7.Sundia MediTech Co Ltd, 917 Halei Rd, Shanghai 201203, Peoples R China; 8.Decibel Therapeut, 1325 Boylston St Suite 500, Boston, MA 02215 USA; 9.Celsius Therapeut, 215 First St, Cambridge, MA 02142 USA |
推荐引用方式 GB/T 7714 | Padyana, Anil K.,Gross, Stefan,Jin, Lei,et al. Structure and inhibition mechanism of the catalytic domain of human squalene epoxidase[J]. NATURE COMMUNICATIONS,2019,10. |
APA | Padyana, Anil K..,Gross, Stefan.,Jin, Lei.,Cianchetta, Giovanni.,Narayanaswamy, Rohini.,...&Smolen, Gromoslaw A..(2019).Structure and inhibition mechanism of the catalytic domain of human squalene epoxidase.NATURE COMMUNICATIONS,10. |
MLA | Padyana, Anil K.,et al."Structure and inhibition mechanism of the catalytic domain of human squalene epoxidase".NATURE COMMUNICATIONS 10(2019). |
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