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Padyana, Anil K; Gross, Stefan; Jin, Lei; Cianchetta, Giovanni; Narayanaswamy, Rohini; Wang, Feng; Wang, Rui; Fang, Cheng; Lv, Xiaobing; Biller, Scott A; Dang, Lenny; Mahoney, Christopher E; Nagaraja, Nelamangala; Pirman, David; Sui, Zhihua; Popovici-Muller, Janeta; Smolen, Gromoslaw A
Nature communications, 01/2019, Letnik: 10, Številka: 1Journal Article
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 Å and 2.5 Å). Comparison with its unliganded state (3.0 Å) 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.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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Vir: Osebne bibliografije
in: SICRIS
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