6OHT

Structure of EBP and U18666A

Summary for 6OHT

• Entry DOI: 10.2210/pdb6oht/pdb
• Descriptor: 3-beta-hydroxysteroid-Delta(8),Delta(7)-isomerase, 3beta-(2-Diethylaminoethoxy)androst-5-en-17-one (2 entities in total)
• Functional Keywords: membrane protein, isomerase, isomerase-inhibitor complex, isomerase/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 3
• Total formula weight: 83850.46

Authors

Long, T.,Li, X. (deposition date: 2019-04-06, release date: 2019-06-19, Last modification date: 2024-11-13)

Primary citation

Long, T.,Hassan, A.,Thompson, B.M.,McDonald, J.G.,Wang, J.,Li, X.
Structural basis for human sterol isomerase in cholesterol biosynthesis and multidrug recognition.
Nat Commun, 10:2452-2452, 2019

PubMed Abstract: 3-β-hydroxysteroid-Δ, Δ-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.

PubMed: 31165728
DOI: 10.1038/s41467-019-10279-w

Experimental method

X-RAY DIFFRACTION (3.2 Å)