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

Author

Listed:
  • Anil K. Padyana

    (Agios Pharmaceuticals)

  • Stefan Gross

    (Agios Pharmaceuticals)

  • Lei Jin

    (Agile Biostructure Solutions Consulting)

  • Giovanni Cianchetta

    (Agios Pharmaceuticals
    KSQ Therapeutics)

  • Rohini Narayanaswamy

    (Agios Pharmaceuticals)

  • Feng Wang

    (Wuxi Biortus Biosciences Co. Ltd.)

  • Rui Wang

    (Wuxi Biortus Biosciences Co. Ltd.
    Xiamen University)

  • Cheng Fang

    (Shanghai ChemPartner Co. Ltd.)

  • Xiaobing Lv

    (Shanghai ChemPartner Co. Ltd.
    Sundia MediTech Company, 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
    Decibel Therapeutics)

  • Gromoslaw A. Smolen

    (Agios Pharmaceuticals
    Celsius Therapeutics)

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.

Suggested Citation

  • 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 & Nelama, 2019. "Structure and inhibition mechanism of the catalytic domain of human squalene epoxidase," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
  • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-018-07928-x
    DOI: 10.1038/s41467-018-07928-x
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    Cited by:

    1. Qian Wang & Ning Liu & Yaming Deng & Yuze Guan & Hongli Xiao & Tara A. Nitka & Hui Yang & Anju Yadav & Lela Vukovic & Irimpan I. Mathews & Xi Chen & Chu-Young Kim, 2023. "Triepoxide formation by a flavin-dependent monooxygenase in monensin biosynthesis," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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