Structural Basis for Human Sterol Isomerase in Cholesterol Biosynthesis and Multidrug Recognition
ARTICLE https://doi.org/10.1038/s41467-019-10279-w OPEN Structural basis for human sterol isomerase in cholesterol biosynthesis and multidrug recognition Tao Long 1, Abdirahman Hassan 1, Bonne M Thompson2, Jeffrey G McDonald1,2, Jiawei Wang3 & Xiaochun Li 1,4 3-β-hydroxysteroid-Δ8, Δ7-isomerase, known as Emopamil-Binding Protein (EBP), is an endoplasmic reticulum membrane protein involved in cholesterol biosynthesis, autophagy, 1234567890():,; oligodendrocyte formation. The mutation on EBP can cause Conradi-Hunermann syndrome, an inborn error. Interestingly, EBP binds an abundance of structurally diverse pharmacolo- gically 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. 1 Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. 2 Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. 3 State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China. 4 Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
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