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Structure and inhibition mechanism of the catalytic domain of human squalene epoxidase.
Nature Communications ( IF 14.7 ) Pub Date : 2019-01-09 , DOI: 10.1038/s41467-018-07928-x Anil K Padyana 1 , Stefan Gross 1 , Lei Jin 2 , Giovanni Cianchetta 1, 3 , Rohini Narayanaswamy 1 , Feng Wang 4 , Rui Wang 4, 5 , Cheng Fang 6 , Xiaobing Lv 6, 7 , Scott A Biller 1 , Lenny Dang 1 , Christopher E Mahoney 1 , Nelamangala Nagaraja 1 , David Pirman 1 , Zhihua Sui 1 , Janeta Popovici-Muller 1, 8 , Gromoslaw A Smolen 1, 9
Nature Communications ( IF 14.7 ) Pub Date : 2019-01-09 , DOI: 10.1038/s41467-018-07928-x Anil K Padyana 1 , Stefan Gross 1 , Lei Jin 2 , Giovanni Cianchetta 1, 3 , Rohini Narayanaswamy 1 , Feng Wang 4 , Rui Wang 4, 5 , Cheng Fang 6 , Xiaobing Lv 6, 7 , Scott A Biller 1 , Lenny Dang 1 , Christopher E Mahoney 1 , Nelamangala Nagaraja 1 , David Pirman 1 , Zhihua Sui 1 , Janeta Popovici-Muller 1, 8 , Gromoslaw A Smolen 1, 9
Affiliation
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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.
中文翻译：
人角鲨烯环氧酶催化域的结构及抑制机制。
角鲨烯环氧化酶 (SQLE)，也称为角鲨烯单加氧酶，催化角鲨烯立体定向转化为 2,3(S)-氧化角鲨烯，这是胆固醇生物合成的关键步骤。SQLE 抑制的目标是治疗高胆固醇血症、癌症和真菌感染。然而，缺乏结构功能理解阻碍了其抑制剂的进一步发展。我们利用小分子抑制剂（2.3 Å 和 2.5 Å）确定了人类 SQLE 催化结构域的第一个三维高分辨率晶体结构。与其未配体状态 (3.0 Å) 的比较揭示了抑制剂结合后的构象重排，从而可以更深入地解释已知的结构-活性关系。我们使用人类 SQLE 结构来进一步了解特比萘芬（一种已批准的针对真菌 SQLE 的药物）的特异性，并提供对临床中遇到的特比萘芬耐药突变体的结构见解。总的来说，这些发现阐明了 SQLE 催化的环氧化反应特异性的结构基础，并使下一代抑制剂的进一步合理开发成为可能。
更新日期：2019-01-09
中文翻译：
人角鲨烯环氧酶催化域的结构及抑制机制。
角鲨烯环氧化酶 (SQLE)，也称为角鲨烯单加氧酶，催化角鲨烯立体定向转化为 2,3(S)-氧化角鲨烯，这是胆固醇生物合成的关键步骤。SQLE 抑制的目标是治疗高胆固醇血症、癌症和真菌感染。然而，缺乏结构功能理解阻碍了其抑制剂的进一步发展。我们利用小分子抑制剂（2.3 Å 和 2.5 Å）确定了人类 SQLE 催化结构域的第一个三维高分辨率晶体结构。与其未配体状态 (3.0 Å) 的比较揭示了抑制剂结合后的构象重排，从而可以更深入地解释已知的结构-活性关系。我们使用人类 SQLE 结构来进一步了解特比萘芬（一种已批准的针对真菌 SQLE 的药物）的特异性，并提供对临床中遇到的特比萘芬耐药突变体的结构见解。总的来说，这些发现阐明了 SQLE 催化的环氧化反应特异性的结构基础，并使下一代抑制剂的进一步合理开发成为可能。
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