2. Academic Validation
  3. Structure and inhibition mechanism of the catalytic domain of human squalene epoxidase

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

  • Nat Commun. 2019 Jan 9;10(1):97. doi: 10.1038/s41467-018-07928-x.
Anil K Padyana 1,  Stefan Gross 2,  Lei Jin 3,  Giovanni Cianchetta 2 4,  Rohini Narayanaswamy 2,  Feng Wang 5,  Rui Wang 5 6,  Cheng Fang 7,  Xiaobing Lv 7 8,  Scott A Biller 2,  Lenny Dang 2,  Christopher E Mahoney 2,  Nelamangala Nagaraja 2,  David Pirman 2,  Zhihua Sui 2,  Janeta Popovici-Muller 2 9,  Gromoslaw A Smolen 2 10
Affiliations

Affiliations

  • 1 Agios Pharmaceuticals, 88 Sidney Street, Cambridge, MA, 02139, USA. [email protected].
  • 2 Agios Pharmaceuticals, 88 Sidney Street, Cambridge, MA, 02139, USA.
  • 3 Agile Biostructure Solutions Consulting, LLC, 8 Harris Ave, Wellesley, MA, 02481, USA.
  • 4 KSQ Therapeutics, 610 Main St, Cambridge, MA, 02139, USA.
  • 5 Wuxi Biortus Biosciences Co. Ltd., 6 Dongsheng West Road, Jiangyin, 214437, China.
  • 6 Department of Stomatology, Xiamen University, 361102, Xiamen, China.
  • 7 Shanghai ChemPartner Co. Ltd., 998 Halei Road, 201203, Shanghai, China.
  • 8 Sundia MediTech Company, Ltd., 917 Halei Road, 201203, Shanghai, China.
  • 9 Decibel Therapeutics, 1325 Boylston St Suite 500, Boston, MA, 02215, USA.
  • 10 Celsius Therapeutics, 215 First Street, Cambridge, MA, 02142, USA.
PMID: 30626872 DOI: 10.1038/s41467-018-07928-x
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.

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