6C6N
Human squalene epoxidase (SQLE, squalene monooxygenase) structure with FAD and Cmpd-4"
Summary for 6C6N
| Entry DOI | 10.2210/pdb6c6n/pdb |
| Related | 6C6P 6C6R |
| Descriptor | Squalene monooxygenase, GLYCEROL, SULFATE ION, ... (7 entities in total) |
| Functional Keywords | cholesterol synthesis pathway, sqle, erg1, fad-dependent monooxygenase, squalene hydroxylase, squalene-2, 3-epoxidase, flavoprotein, oxidoreductase-oxidoreductase inhibitor complex, flavoprotein-inhibitor complex, flavoprotein/inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 109122.65 |
| Authors | Padyana, A.K.,Jin, L. (deposition date: 2018-01-19, release date: 2019-01-16, Last modification date: 2024-03-13) |
| Primary citation | 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 Cited by 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: 30626872DOI: 10.1038/s41467-018-07928-x PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.3 Å) |
Structure validation
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