Structure and inhibition mechanism of the catalytic domain of human squalene epoxidase

Anil K. Padyana (), Stefan Gross, Lei Jin, Giovanni Cianchetta, Rohini Narayanaswamy, Feng Wang, Rui Wang, Cheng Fang, Xiaobing Lv, Scott A. Biller, Lenny Dang, Christopher E. Mahoney, Nelamangala Nagaraja, David Pirman, Zhihua Sui, Janeta Popovici-Muller and Gromoslaw A. Smolen
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Anil K. Padyana: Agios Pharmaceuticals
Stefan Gross: Agios Pharmaceuticals
Lei Jin: Agile Biostructure Solutions Consulting
Giovanni Cianchetta: Agios Pharmaceuticals
Rohini Narayanaswamy: Agios Pharmaceuticals
Feng Wang: Wuxi Biortus Biosciences Co. Ltd.
Rui Wang: Wuxi Biortus Biosciences Co. Ltd.
Cheng Fang: Shanghai ChemPartner Co. Ltd.
Xiaobing Lv: Shanghai ChemPartner Co. Ltd.
Scott A. Biller: Agios Pharmaceuticals
Lenny Dang: Agios Pharmaceuticals
Christopher E. Mahoney: Agios Pharmaceuticals
Nelamangala Nagaraja: Agios Pharmaceuticals
David Pirman: Agios Pharmaceuticals
Zhihua Sui: Agios Pharmaceuticals
Janeta Popovici-Muller: Agios Pharmaceuticals
Gromoslaw A. Smolen: Agios Pharmaceuticals

Nature Communications, 2019, vol. 10, issue 1, 1-10

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-018-07928-x

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