6oht
Structure of EBP and U18666AStructure of EBP and U18666A
Structural highlights
Disease[EBP_HUMAN] MEND syndrome;X-linked dominant chondrodysplasia punctata. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. Function[EBP_HUMAN] Catalyzes the conversion of Delta(8)-sterols to their corresponding Delta(7)-isomers.[1] [2] [3] Publication Abstract from PubMed3-beta-hydroxysteroid-Delta(8), Delta(7)-isomerase, known as Emopamil-Binding Protein (EBP), is an endoplasmic reticulum membrane protein involved in cholesterol biosynthesis, autophagy, oligodendrocyte formation. The mutation on EBP can cause Conradi-Hunermann syndrome, an inborn error. Interestingly, EBP binds an abundance of structurally diverse pharmacologically active compounds, causing drug resistance. Here, we report two crystal structures of human EBP, one in complex with the anti-breast cancer drug tamoxifen and the other in complex with the cholesterol biosynthesis inhibitor U18666A. EBP adopts an unreported fold involving five transmembrane-helices (TMs) that creates a membrane cavity presenting a pharmacological binding site that accommodates multiple different ligands. The compounds exploit their positively-charged amine group to mimic the carbocationic sterol intermediate. Mutagenesis studies on specific residues abolish the isomerase activity and decrease the multidrug binding capacity. This work reveals the catalytic mechanism of EBP-mediated isomerization in cholesterol biosynthesis and how this protein may act as a multi-drug binder. Structural basis for human sterol isomerase in cholesterol biosynthesis and multidrug recognition.,Long T, Hassan A, Thompson BM, McDonald JG, Wang J, Li X Nat Commun. 2019 Jun 5;10(1):2452. doi: 10.1038/s41467-019-10279-w. PMID:31165728[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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