6C6R

Human Squalene Epoxidase (SQLE, Squalene Monooxygenase) structure with FAD

6C6R の概要

• エントリーDOI: 10.2210/pdb6c6r/pdb
• 関連するPDBエントリー: 6C6N 6C6P
• 分子名称: Squalene monooxygenase, FLAVIN-ADENINE DINUCLEOTIDE, 3-[(3-CHOLAMIDOPROPYL)DIMETHYLAMMONIO]-1-PROPANESULFONATE, ... (5 entities in total)
• 機能のキーワード: cholesterol synthesis pathway, sqle, erg1, fad-dependent monooxygenase, complex, flavoprotein, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 107879.02

構造登録者

Padyana, A.K.,Jin, L. (登録日: 2018-01-19, 公開日: 2019-01-16, 最終更新日: 2024-03-13)

主引用文献

Padyana, A.K.,Gross, S.,Jin, L.,Cianchetta, G.,Narayanaswamy, R.,Wang, F.,Wang, R.,Fang, C.,Lv, X.,Biller, S.A.,Dang, L.,Mahoney, C.E.,Nagaraja, N.,Pirman, D.,Sui, Z.,Popovici-Muller, J.,Smolen, G.A.
Structure and inhibition mechanism of the catalytic domain of human squalene epoxidase.
Nat Commun, 10:97-97, 2019

PubMed 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.

PubMed: 30626872
DOI: 10.1038/s41467-018-07928-x

実験手法

X-RAY DIFFRACTION (3 Å)