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
  • 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.